|Year : 2020 | Volume
| Issue : 1 | Page : 16-20
Asthma and aspergillosis: Which One causes another
Roaa Noori Ali, Ali Abdul Hussein S. Al-Janabi
Department of Microbiology, College of Medicine, University of Karbala, Karbala, Iraq
|Date of Submission||10-Oct-2019|
|Date of Acceptance||05-Jan-2020|
|Date of Web Publication||17-Mar-2020|
Prof. Ali Abdul Hussein S. Al-Janabi
Department of Microbiology, College of Medicine,University of Karbala, Karbala
Source of Support: None, Conflict of Interest: None
The respiratory system of the human body is always under exposure to a great number of fungal spores every day. Asexual spores of Aspergillus are the most frequent type occurring in various environments. Inhalation of these spores can lead to various undesirable effects in the airway. Infection in the form of aspergillosis is one type of harmful effect of inhaled spores, especially in immunocompromised patients, while sensitization is a second type after long-term exposure to Aspergillus spores. In some cases, sensitization can develop into a various types of allergic diseases such as asthma. Otherwise, aspergillosis can be initiated in many asthmatic patients, which make asthma a predisposing factor for aspergillosis. In conclusions: Asthma and aspergillosis have shared responsibility to form each other in reversible relationship.
Keywords: Allergic bronchopulmonary aspergillosis, aspergillosis, Aspergillus, asthma
|How to cite this article:|
Ali RN, S. Al-Janabi AA. Asthma and aspergillosis: Which One causes another. Biomed Biotechnol Res J 2020;4:16-20
| Introduction|| |
Asthma is a chronic inflammatory disease of the airway caused by multifactor agents with characteristics of variable obstruction and resistance in airflow hyperresponsiveness which refers to resistance in air flow and smooth muscle sensitivity to bronchoconstricting stimuli., In the USA, it is ranked eighth among diseases needing a doctor's visit. Its prevalence and mortality has sharply increased over the last decades. There are approximately 300 million people worldwide suffering from asthma with 180,000 deaths annually and numbers increase by 50% every decade. Based on estimation of the Institute for Health Metrics and Evaluation, a gradual increasing in morbidity and mortality of asthma with a prevalence of 4% is specifically found in African adults.
Sensitization to the fungal allergen is the most effective factor to trigger or worsen asthma., Antigens of Aspergillus species are a common type of allergen responsible for developing or stimulating of such allergic diseases., Exposure of the respiratory epithelial tissues to the Aspergillus antigen may initiate from the entry of inhaled spores or from colonization of fungi in the pulmonary system in the form of aspergillosis disease.,,,, There are different types of pulmonary aspergillosis with variable invasive ability into the pulmonary system., Allergic bronchopulmonary aspergillosis (ABPA) is the most frequent type of aspergillosis recognized to associate with asthma, especially that caused by Aspergillus fumigatus.,,,,
A strong correlation between asthma and aspergillosis makes it difficult to understand which one has more effect on the other. Many clinical evidences support that aspergillosis plays a major role in asthma., Others demonstrated that asthma is the main predisposing factor for development of aspergillosis.,, This review tries to clarify the actual relationship between asthma and aspergillosis based on many related factors associated with each of them.
| Asthma|| |
Asthma is considered one of chronic inflammatory diseases that may result from the interaction of environment and genetic factors. Most clinical features of asthma are represented by airway obstruction, bronchial hyperresponsiveness and greater airway wall thickening, with episodes of various symptoms, including chest tightness, wheeze, cough, and shortness of breath., Epithelial destruction of the airways, especially ciliated cells, is also recognized in most asthmatic patients.
Asthma more commonly develops in females with more serious symptoms and less comfortable life than in males. Estrogen in females could be responsible for this through its anti-inflammatory activity by decreasing the production of tumour necrosis factor alpha, expression of interferon-γ and the activity of natural killer cells. Thus, management of asthma in females should be focused on the relationship between variation in hormones and asthma symptoms. Race has no great effect on the severity of asthma, while other factors may have a role to increase severity such as obesity, change in diet, depression, and gastroesophageal reflux disease., Rhinitis can also have a role in the development of asthma.
The prevalence of asthma has increased all over the world, especially in Western countries, while less common in developing countries. Severe types of asthma can increase the death rate as was found in the UK when it causes death in about 1500 patients per year. Children are higher incidence than adults in development of asthma, especially at age 0–17 years. Prevalence of uncontrolled asthma was estimated to be 35% of children with nonrespiratory complaints, while it was at 54% in those with respiratory complaints. Infants are also at risk of developing asthma, which may result from exposure in utero to various factors.
Control of asthma is usually obligatory requirement for patient management. Such control should include management of rhinitis, smoking and low adherence to inhaled corticosteroid. Therefore, control of asthma makes life better with less time spent on emergency and hospital rooms than those with uncontrolled type.
| Asthma and Fungi|| |
Fungi are one of the most common types of organisms that can be found everywhere on the earth. They contain diverse species with an ability to live on a variety of organic compounds; some are used for food, some are decomposers and recyclers, and some have a potential capacity to cause diseases in animals and plants. Thus, continuous exposure to fungal elements is considered a fact that humans should live with. Such exposure can lead to three main adverse effects: infections, allergic diseases, and toxicity with irritable effects. Asthma is one type of allergic disease that can develop or increase its severity in the presence of fungi. Although asthma is a multifactorial disease, fungi as a unique exogenous causative agent for it is not completely proved, may be because exposure to fungi is highly variable in time or density or hard to measure. Diverse distribution of fungi outdoors and indoors can also be considered an important factor to development of asthma. Most of asthmatic severity is associated with exposure to outdoor fungi, while the data about the contribution of indoor fungi are less strong. However, dampness conditions in an indoor environment may stimulate asthma to become worse in the presence of fungi.
Accumulated evidences currently support the association between mold exposure and asthma., This type of association may be built on the fact that inhalation of fungal spores will lead to fungal allergy or sensitization or may cause allergic bronchopulmonary mycosis. The mortality risk among asthmatic people can increase by 2.16 times if exposure to not <1000 spore/m 3. The prevalence of fungal sensitization is usually recorded at high percentage all over the world. It is found relatively higher (3%–52%) among the asthmatic African population. Evidence of the role of fungi to cause asthma is supported by an observation that asthma peak is elevated with the high air contents of mold in summer and autumn, while it declines when fungi have low count during snow season. Moreover, the admission of asthmatic patients into hospital, especially those at age 16–40 years, was found to be in greater number during the mold season of July and October.
Fungi have the ability to induce asthma when they colonize the human body for a long time. This may cause damage in the airway tissue via production of toxins or volatile organic compounds or even stimulate an auto-reactive response by fungal proteins antigenically similar to that of the human body., Although both fungal allergy and sensitization developed through immune-mediated response to fungi, inflammation with tissue damage may only result from fungal allergy, while fungal sensitization is characterized by the absence of such events and only indicated by elevated level of fungal-specific immunoglobulin E (IgE) or cutaneous hyperreaction to fungal antigen.,, Thus, fungal sensitization can be diagnosed by performing skin prick tests (SPT) with fungal antigens or by measuring the level of specific-IgE in blood., Based on a skin test, about 63 cases from 645 asthmatic patients were found sensitive to various species of fungi. However, perfect diagnosis of asthma with fungal exposure remains dependent on the results of clinical, radiological and immunological features all together.
Fungal allergen, the antigen of fungi causing allergy, is the most effective factor to trigger or worsen asthma., Five groups of allergen are diagnosed to have an effect on asthmatic individuals, including two enzymes (protease and glycosidases), which have a direct effect on the host, and three metabolized proteins association with spore germination. Long-time exposure of the human body to these compounds either by directly entering as inhalation fungi or their release from colonization in tracheobronchial tracts will certainly stimulate asthma symptoms in the lower airway parts.,, During the time of exposure to fungal allergen, mild asthma can firstly develop without effect on lung functions, but over the time clinical symptoms such as airflow obstruction, bronchiectasis and chronic pulmonary aspergillosis (CPA) will gradually increase to form severe asthma. Sensitization in asthmatic patients to fungal exposure can develop toward one or more fungal allergens depending on the variety of fungi and without denying the possibility of occurrence of cross-reactivity between these various allergen sources. Currently, a new term called severe asthma with fungal sensitization (SAFS) has become very common as an indicator for the association between fungal sensitization and this severe type of asthma.,, The main characters of SAFS are suffering from severe asthma with <1000 IU/ml of total IgE. The SAFS usually causes high rates of death and hospital admissions of adults or bronchial allergy in children., More than 6.5 million people suffering from SAFS with up to 50% of asthmatic adults are need secondary care for fungal sensitization.
There are too many species of fungi that have the capacity to cause sensitization in the human body of the asthmatic individuals, but the specific one for SAFS is currently unknown. Species of Aspergillus were recorded to be the most important agents for such sensitization in asthmatic people., Positive sensitization of patients with severe asthma to fungal species showed higher to Aspergillus spp. (45%), followed by six other fungal species. This also was observed in an Egyptian asthmatic population when sensitization to Aspergillus spp. (41.8%) was higher than the other three species. Penicillium spp. are also considered a sensitizing agent in various ages of asthmatic patients starting with infants., Of 121 patients with severe asthma, 29% of them have sensitivity to P. notatum, while it represented 33.4% from 645 asthmatic patients with predominant allergic factor. Several other fungi also have the sensitization effect associated with asthma such as Alternaria spp., Candida albicans, Trichophyton spp., Cladosporium spp. and Helminthosporium spp.,,, Thus, management of fungal allergy in patients with asthma should be done in almost five steps; avoid of fungal exposure; keep inflammatory reaction under control; enhance airway flow by reducing obstruction and the amount of mucus; and control of bacterial infection.,
| Aspergillusand Aspergillosis|| |
Aspergillus is one of the large groups of saprophytic fungi containing >180 species; of which a fifth of them have the ability to cause human and animal diseases., It wide distribution in outdoor environments as saprophytic fungi which live on organic materials in soil, plant debris, and decaying plants and animals., Indoor environments also contain Aspergillus as in factories of food industry, hospitals and our homes., Asexually produced conidia are the most common shared feature in all Aspergillus species. Conidia, which are usually produced as interconnected chains on broadly clavate structure on the vesicle of fungal body, are usually hyaline color when present singly and variable colors when collected in clusters.,
Aspergillosis is a fungal disease mainly caused by several members of Aspergillus., Asexual conidia of Aspergillus are usually considered the most causative agent for this disease due to their production in thousands, while sexual spores have a minor role in diseases because few are produced. Separation of conidia from producing fungi is accomplished under the effect of strong air currents or by animal activities, to facilitate dispersing such small conidia by air and distributing them in outdoor and indoor environment., Thus, conidia can enter into the respiratory tract of the human body by inhalation of contaminated air, but without development any diseases in most people with a good immune system.,, Alveolar macrophage and epithelial cells normally destroy inhaled conidia. Any weakness in immune system or the presence of other underlying conditions can facilitate development of aspergillosis after germination of conidia into hypha.,,, However, immunocompromised conditions may result from various factors such as cancers (leukemia, Aplastic anemia), treatment with immunosuppressive drugs (chemotherapy or corticosteroids for various disorders as with organ transplantation and allergic diseases), viral infections such as HIV and cytomegalovirus, and occurrence of chronic lung diseases like asthma, TB, or cystic fibrosis. Generally, the common route of entering of Aspergillus conidia is the respiratory tract, while other sites such as skin, gastrointestinal, kidney, eye, and peritoneum are less commonly described in association with infections. Small size, thermotolerance, and hydrophobic nature of conidia are considered important factors in causing aspergillosis. Aspergillus species also have other virulence factors which play a role in the development of different types of aspergillosis, including production of proteases, antioxidants, pigments, adhesins, siderophores, and mycotoxins., A. fumigatus is considered the most virulent species with an ability to cause a wide range of aspergillosis (90%), especially in immunocompromised patients.,, Many characters can facilitate A. fumigatus to be the most dangerously infectious species, including its production of small size green echinulate conidia (2.5–3 mm in diameter) with large numbers of spores, tolerance to the temperature of the human body, secretion of protease, its highly antigenic nature, and drug-resistance to common antifungal agents.,, Other species of Aspergillus rather than A. fumigatus are also recorded in association with aspergillosis such as A. flavus, A. niger, A. terreus, A. nidulans, and A. ustus. Otherwise, fungal groups that differ from Aspergillus could play a role in the development of aspergillosis as with zygomycetes and Fusarium, especially in aspergilloma (fungal ball).
Recently, aspergillosis has become a well known type of fungal disease due to increased use of immunosuppressive drugs. Several types of infections and allergic diseases have been identified resulting from the direct pathogenic activity of Aspergillus spp. or from host sensitization to this type of fungi such as asthma, allergic sinusitis and alveolitis.,,, High morbidity and mortality rate are continually recorded for aspergillosis. Thus, aspergillosis which may involve any tissue in the human body mainly depend on the immune state of the host and pulmonary structure., It can, in general, be classified into invasive and noninvasive diseases. Invasive aspergillosis (IA) has been observed with fourfold increase in the last 12 years. Actually, the great numbers of aspergillosis types are difficult to classify because of their cross-interaction in clinical characters, pathological features, and diagnostic properties. Aspergilloma, as an example, is characterized by noninflammatory nature, while it becomes inflamed, even slightly, in the presence of some conditions. However, aspergillosis can be classified based on the site of infection in the pulmonary tract and clinical features into: IA such as invasive pulmonary aspergillosis, chronic aspergillosis such as aspergilloma and CPA, and allergic aspergillosis such as ABPA., Other types of aspergillosis can include any of these three main groups.
| Asthma and Aspergillosis|| |
Hundreds of Aspergillus spores are inhaled into the respiratory tract every day without any effects on human health. This view will change in a person with an atopic disease such as asthma. Aspergillosis is one of the important types of fungal infection strongly associated with asthma. The epithelial cells of the respiratory tract become sensitized after any contact with Aspergillus antigen leading to development of ABPA or SAFS.,, Thus, individuals with allergic asthma are always under the risk of developing pulmonary aspergillosis. Inflammation in the airway of patients with asthma increases in level after inhalation of Aspergillus antigens.
ABPA is the most frequent type of aspergillosis recognized to associate with asthma.,,, This is clear when the presence of asthma becomes one of the important criteria to diagnosis ABPA and because of that any patients with asthma should be expected to have such type of aspergillosis disease, especially those with poor response to corticosteroid treatment.,, An eosinophilic asthmatic patient under treatment of mepolizumab was diagnosed to have ABPA. A positive result for ABPA is also found in 40.4% of asthmatic patients. The prevalence of ABPA in bronchial asthma is recorded in about 12.9% based on worldwide estimations from 1965 to 2008.
Antigenic structure of A. fumigatus is mostly responsible for sensitization of asthmatic patients to Aspergillus exposure.,,, This fungus was diagnosed in 63% of IgE-sensitized patients with asthma. Sensitization to fungal exposure can increase the risk value for development of ABPA in 1%–2% of patients with asthma and in 7%–9% with cystic fibrosis. Clinical features of association between A. fumigatus and asthma are usually represented by clearly observable bronchiectasis with greater airflow obstruction. In general, most characters of sensitization in asthmatic patients to A. fumigatus, including lower lung function, neutrophilic airway inflammation, more bronchiectasis and highest level of A. fumigatus–IgE.
SPT is most significant test for detecting sensitization to A. fumigatus infection. It can divide asthmatic patients into reactors and nonreactors groups. About 46% of asthmatic patients have a positive SPT for Aspergillus and some of them have ABPA based on positive Aspergillus-precipitin test and radiological features. In North India, 35.1% of 350 asthmatic patients showed positive SPT and 21.7% of them had ABPA. Another study in India from 2012 to 2013 revealed that 59.5% of asthmatic patients have sensitization to Aspergillus according to the results of SPT and spirometry. About 11.7% of the Asian population with severe asthma showed positive SPT to Aspergillus antigens which was used as indicator for development of SFSA. On the other hand, intradermal test for diagnosis of hypersensitivity to Aspergillus exposure can be more sensitive than SPT.
Avoiding exposure to Aspergillus antigens is a master key to limit the severity of asthma in most patients. Antifungal treatment for at least 3 months, for example, with voriconazole and systemic steroids, is important to moderate the severity of sensitization to A. fumigatus.,
In conclusion; several accumulation evidences currently support the association between mold exposure and asthma. Aspergillosis can introduce the facility to develop asthma after long-term exposure to Aspergillus antigens. Asthma can also encourage infection with aspergillosis in many cases. Thus, asthma and aspergillosis have shared responsibility to form each other in reversible relationship.
The authors want to introduce a great thankfulness to Mr. Philip Smith for his assistance in language corrections.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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