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    The changing face of asthma and its relation with microbes



    Author links open overlay panelChris S.EarlRobert P.Ryan
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    https://doi.org/10.1016/j.tim.2015.03.005
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    Open Access funded by Wellcome Trust
    Under a Creative Commons licenseopen access
    Highlights

    Bacterial respiratory tract infections have a strong association with worsening or increased severity of symptoms in asthma patients.


    The asthma airway is characterized by an altered microbiota composition, compared with healthy individuals.


    Microbial stimuli and the composition of the airway microbiota can contribute to the shaping of inflammatory responses seen in asthma.


    Approaches to rapidly diagnose or modulate the microbiota associated with the asthmatic airway may represent powerful tools to improve disease prognosis.


    During the past 50 years, the prevalence of asthma has increased and this has coincided with our changing relation with microorganisms. Asthma is a complex disease associated with local tissue inflammation of the airway that is determined by
    environmental, immunological, and host genetic factors. In a subgroup of sufferers, respiratory infections are associated with the development of chronic disease and more frequent inflammatory exacerbations. Recent studies suggest that these infections
    are polymicrobial in nature. Furthermore, there is increasing evidence that the recently discovered asthma airway microbiota may play a critical role in pathophysiological processes associated with the disease. Here, we discuss the current data regarding
    a possible role for infection in chronic asthma with a particular focus on the role bacteria may play. We discuss recent advances that are beginning to elucidate the complex relations between the microbiota and the immune response in asthma patients. We
    also highlight the clinical implications of these recent findings in regards to the development of novel therapeutic strategies.

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    Keywords
    airwayallergensasthmainfectioninflammationmicrobiota
    The human microbiome and its interaction with the host
    Medical and hygiene advances over the past 150 years, such as sanitation measures, vaccines, and antibiotics, have helped arm the fight against infectious microorganisms, curbing infant mortality and greatly increasing life expectancy. However, in recent
    years, it has become clear that humans have, during the course of their evolution, developed an essential symbiotic relation with microorganisms and this is redefining the way we view infectious disease [1]. It is now understood that we are host to a
    vast number of bacterial, fungal, viral, and eukaryotic cohabiters termed the microbiota. In the simplest terms, the microbiota can be defined as the microbes associated with a particular environmental niche. Although the term microbiota has been used
    for decades, clinical and scientific interest in human-associated microbiota is more recent and has been further stimulated by projects like the Human Microbiome Project or sub-projects like the gut microbiome project MetaHIT. These studies utilizing
    advanced molecular techniques have generated unprecedented insight into the complexity and diversity of microbial communities that exist on and within humans. It is clear that these microbial communities, particularly in the gut, play a key role in the
    protection from pathogenic organisms and the development and maintenance of immune responses. The study of the role of the gut microbiota in modern diseases such as asthma, obesity, juvenile diabetes, and specific cancers has revealed that perturbations
    to microbial communities have a profound effect on disease development and treatment response [1–3].

    Technological advances have resulted in the advent of high-resolution molecular investigations into the airway microbiota in pulmonary health and/or disease. Given that the lungs represent one of the largest interfaces between the human host and the
    external environment, being exposed to >8000 l of inhaled air each day [4], it is unsurprising that a direct connection between aberrant microbial colonization of the airways has been shown to contribute to the development of chronic inflammatory
    diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) [5].

    Until recently, the understanding of the role bacteria play in asthma, another chronic lower airway disease, has lagged behind its counterparts. However, clinicians and researchers have begun to benefit from this deeper understanding to re-evaluate and
    redirect efforts to understand the relations between asthma and microbial colonization [5]. This has been stimulated by the fact that >300 million people worldwide suffer from this disease, which results in an economic burden of >$80 billion per year in
    the US alone.

    In this review, we discuss recent studies that have shed light on the association of microorganisms with asthma and the potential interactions between the airway microbiota and the immune system. We also discuss how a deeper understanding of the
    microbiota within the asthmatic airway may provide potential therapeutic avenues.

    The asthma airway and associated microbes
    Specific microorganisms and asthma disease development
    The US Department of Health and Human Services defines asthma as ‘an inflammatory disease of the airways with generally reversible air flow obstruction and airway hyper-responsiveness causing episodic respiratory symptoms’, in which many cells and
    cellular elements play a role [6]. The chronic inflammation is associated with airway hyper-responsiveness and leads to recurrent episodes of exacerbation marked by wheezing, breathlessness, chest tightness, and coughing [7]. Historically, the
    contribution of bacteria and other microbes to asthma pathogenesis was investigated using: (i) traditional culture-dependent approaches to sample the airway; (ii) serological testing to identify microbe specific antibodies in the serum; and (iii) by
    species-targeted PCR (7). The importance of viral infections as a source of asthma exacerbation and chronic inflammation of the airways in children and adults is well demonstrated [8,9]. The potential contribution of fungal infection to asthma is less
    well understood (Box 1), and in the case of bacterial infections, it is now felt that they can contribute to the development of stable asthma and acute exacerbations [10].

    Box 1
    Fungus in asthma

    Culturing of fungi from airway samples is challenging due to slow growth, specific media requirements, and the lack of quantitative methods, which is due in part to filamentous morphologies [56–58]. Taken together, this has made it difficult to
    describe fungal species and their relative burdens in respiratory disease.

    Although the fungal microbiota of the asthmatic respiratory tract has not been well characterized to date, there is evidence that specific fungal species can play a part in the clinical progression of disease [59]. Fungi can cause problems in the airways
    of asthma patients in two ways: by acting as allergens or as pathogens causing infection, with many fungi being able to do both and often concurrently.

    It is well documented that the spores of several filamentous species within the genera of Aspergillus, Alternaria, Cladosporius, Penicillium, and Didymella (phylum Ascomycota) may act as allergens and initiate asthma development in atopic individuals.
    Importantly, fungal infection and exposure have already been linked to several clinical consequences in asthmatics including deterioration of lung function, increased hospital admission, and even mortality. One of the most documented fungal infections
    observed in asthmatics is allergic bronchopulmonary aspergillosis (ABPA), caused by colonization of the lower respiratory tract with Aspergillus spp. In this situation, the fungus acts as both a source of allergen and as a pathogen [60]. ABPA presents
    itself by a range of clinical features including asthma exacerbation, recurrent pulmonary infiltrates, elevated total serum IgE, elevated Aspergillus-fumigatus-specific IgE or IgG, central bronchiectasis, eosinophilia, and mucous plug production.
    Furthermore, ABPA is difficult to predict given that allergens produced by A. fumigatus are diverse in nature and the dormant spores can evade host defense mechanisms until conditions are suitable for germination [60]. Fungi have also been associated
    with severe asthma termed ‘severe asthma with fungal sensitization’ (SAFS) [61]. SAFS is diagnosed by the presence of severe asthma, fungal sensitization, and the absence of ABPA. Because of the paucity of data and ambiguity in diagnostic criteria,
    SAFS is currently classed as a diagnosis of exclusion rather than a specific entity.

    Recent studies have suggested the possible benefit of antifungal therapy in the treatment of asthmatics, with clear improvements seen in lung function, even when fungal species have not been cultured or detected from airway secretions [56]. Although
    little is known of the airway fungal community in the pathogenesis of asthma, these observations suggest that rigorous study should be undertaken. This is even more important given recent studies highlighting the complexity of fungal communities found in
    the oral cavity of healthy individuals [59], the lower airways of CF, and in COPD patients [56–58,62] using pan-fungal primer amplification followed by pyrosequencing. These landmark studies provide the initial standard for studying the fungal
    microbiota along the respiratory tract. Taken together, it is clear that future examination of the fungal microbiota along the respiratory tract in relation to asthma inflammation and phenotypes could be of great interest. Further studies will be
    required to characterize the impact that fungal colonization has on the bacterial communities associated with the asthma airway and the potential cross-kingdom interactions that may occur.

    Despite the lack of definitive evidence, many controlled clinical studies have demonstrated an association between chronic stable asthma and bacteria [11–13], as infected subjects were found to have elevated markers of inflammation, increased severity
    of obstruction identified by FEV1 (forced expiratory volume in one second), higher daytime symptom score, and required high doses of inhaled corticosteroids in comparison with noninfected controls. A strong connection between acute exacerbations of
    asthma and infection with Chlamydia pneumoniae and/or Mycoplasma pneumoniae has also been reported [14], however, there is insufficient data to allow for definite conclusions about the role of such bacteria in late asthma development [15].

    Evidence is also available suggesting that exposure to Staphylococcus aureus and/or its enterotoxins function as an environmental risk factor for the development and severity of asthma [16]. The locally or systemically released enterotoxins show
    superantigen activity and may provoke eosinophilic stimulation leading to deterioration of upper and lower respiratory tract atopic diseases [16]. Specific antibodies against S. aureus enterotoxins are more likely to be found in patients with asthma [16].

    Other respiratory bacteria such as Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae have been shown to cause severe persistent wheeze in children [17]. It was also found that neonates colonized in the pharyngeal region are under
    increased risk for recurrent wheeze and asthma within the first 5 years of life [17]. Particularly evident is the association of these pathogens with a subset of stable asthma, known as neutrophilic asthma, where inflammation is primarily mediated by
    neutrophils and less by eosinophils. H. influenzae was isolated from the airways of patients with neutrophilic asthma, and infection-induced inflammation [17].

    Overall, this work has shown that acute respiratory infections by specific bacteria trigger asthma exacerbations through colonization or infection of the airway. However, it is still unclear and much argued whether these single bacterial infections are
    true causative agents of asthma exacerbation or act as markers for an increased risk of asthma onset [5]. Furthermore, it is not clear what role changes to airway architecture as a result of infection-related damage may impinge upon the future
    development of airway disease and the susceptibility to future infection. The interpretation of these observations has become even more complex in light of the revelation that the airways, that were once assumed to be sterile, have a diversity of
    microorganisms associated with them in asthmatic patients.

    Microbiota associated with the asthmatic airways
    As discussed above, the role of microbial infection in asthma pathogenesis remains unclear. However, the developments in defining the human microbiota have demonstrated that the composition of bacterial communities colonizing mucosal surfaces, rather
    than simply the presence of individual species, can be important in defining states of health or disease. Researchers have been utilizing new high-resolution microbial profiling methods to describe the microbial composition of the asthmatic lung (Box 2).
    Results from these studies in the past 5 years indicate that the composition of the bacterial microbiota detected from the airways of asthmatic patients differs in comparison to those of healthy subjects, although there are variations in the details of
    these findings [5,12,18], likely reflecting the heterogeneity across asthmatic populations.

    Box 2
    Characterizing the airway microbiota

    Culture-dependent approaches have proved useful clinical tools in the detection and characterization of specific microbes present in the respiratory tract, which are responsible for infection [63]. Despite limitations, these methods have been crucial for
    studying the function of community members. However, the selectivity of culture media and the fastidious nature of many microbes have resulted in many important microbiota members being overlooked. In recent years, application of culture-independent
    methods such as microarray hybridization and DNA sequencing technologies has given greater detail and information regarding airway-associated microbial communities [50]. These approaches as well as determining identity and abundance of the microbiota
    present can provide the researcher with information concerning richness, evenness, and dominance. These measures can in some cases be clinically edifying.

    Studying the microbiota of the airways is considered far more problematic than the gut due to the lower burden of biological material and the risk of contamination from the upper airway during sampling. Therefore, it is proposed that lower and upper
    respiratory samples are obtained from each patient. Several materials that are collected routinely by scientists from the respiratory tract include sputum, bronchial brushings and BAL. Sputum is obtained by induced coughing in subjects that results in
    the expectoration of mucus from the lower airways. Sputum is a useful material because it contains immune system components as well as host and bacterial products, including RNA, which can be used to infer the functional properties of communities.
    Bronchial brushings are obtained by passing a protected bronchoscopy cytology brush down the endotracheal tube until resistance is felt. Resistance indicates that the brush has reached the end of the trachea; at this point the brush is extended beyond
    the tip of the bronchoscope and past the end of the protective sheath and moved back and forth on the surface of the airway mucosa to collect the sample. The brush is then retracted into the sheath before being retracted through the bronchoscope to
    minimize contamination of the lower airway sample. BAL involves a bronchoscope being passed through the endotracheal tube and into the bronchus. A saline solution is then delivered through the bronchoscope and aspirated back up into a container.

    Recently, Rogers and colleagues proposed several criteria that should be considered when determining the microbiota of the airway [49]. These included the following. (i) Respiratory material collection can be done in several ways for microbiota studies.
    Regardless of the material collected, it is important to consider the ease, safety, reproducibility, and the potential for contamination. (ii) Sample heterogeneity is also an important consideration if the samples are collected spatially and temporally.
    This depends on the research question being addressed. (iii) Nucleic acid extraction becomes paramount once sample material has been collected. Several studies have examined the importance of deploying stringent extraction procedures. Most have
    illustrated the ease at which distortion can creep into microbiota profiles due to poor, inconsistent or less than rigorous nucleic acid extraction. (iv) Methods for generating microbiota profiles are commonly carried out using generation of 16S rRNA
    clone libraries, terminal RFLP analysis, microarray hybridization, 16S rRNA phylogenetic microarray analysis, or deep sequencing of 16S rRNA amplicon pools. Although the choice of method deployed typically depends on the researchers budget and time
    required, ideally, this choice should be driven by the primary hypothesis to be addressed.(v) Analyzing the resulting data in an informed and relevant manner is imperative. Although there are numerous methods for data analysis available, the processing
    should take into account the potential for spurious signals generated by the profiling method, the potential for contamination during the processing of the samples, and the potential of imperfect taxa identification.

    These recently highlighted criteria for assessment of airway microbiota are rather time-consuming and the research community has called for greater standardization and documentation of microbiota profiling methods, particularly regarding work aimed at
    gaining clinical insight into respiratory disease.

    One of the landmark studies that utilized 16S rRNA clone libraries to examine the respiratory samples from adults and children with asthma found the lung bacterial community to contain members of the Proteobacteria phylum, in particular, Haemophilus spp.,
    Neisseria spp., and Moraxella spp. Although the resolution of this approach is lower than many newer profiling methods, it did find that these strains were more commonly found in asthmatics than the healthy controls tested [19]. A subsequent study of
    bronchial brushings from 75 patients with mild to moderate asthma, using a higher-resolution 16S rRNA phylogenetic microarray platform to assay the airway microbiome, found 100 bacterial taxa that were strongly correlated to airway hyper-responsiveness [
    11]. This study like others found that members of the phylum Proteobacteria were significantly enriched in asthmatics and also included families of potential pathogenic bacteria such as Haemophilus and Streptococcus spp. More recently, an examination of
    induced sputum samples from treatment-resistant severe asthmatics during a non-exacerbation phase of their disease using lower-resolution terminal restriction fragment length polymorphism (T-RFLP) analysis revealed again that patient airway colonization
    was predominantly with Haemophilus spp., Streptococcus spp., or M. catarrhalis[20].

    Studies involving larger numbers of asthmatic patients have observed relations between the clinical outcome and airway microbiota diversity [11]. One of the most comprehensive studies, which examined the microbiota profile of 65 adults who suffered from
    suboptimally controlled asthma showed positive correlation between the abundance of specific airway microbiome members (Comamonadaceae, Sphingomonadaceae, and Oxalobacteraceae) and the degree of airway hyperactivity. Although correlation is not causality,
    it suggests that the presence of specific microbial species in the lower airway is associated with the degree of bronchial hyper-responsiveness, a key feature of asthma [11]. More recently, in patients with severe asthma, relations have been reported
    between airway microbiota and body mass fluctuations [11], as well as neutrophils and interleukin (IL)-8 accumulation in sputum [18]. These relations may influence the type or degree of airway inflammation seen in certain patients and may contribute to
    the complexity in defining phenotypes within asthma.

    Although all these studies describe extensive diversity in the airways of examined asthmatics, it is important to note that little consideration was given to the impact that patient treatments such as inhaled corticosteroids, bronchodilators, and
    antibiotic treatments had on these results. The first studies addressing this gap in our knowledge was carried out using 16S rRNA profiling of DNA extracted from bronchoalveolar lavage (BAL) fluid to compare the airway microbiota of corticosteroid-
    resistant and corticosteroid-sensitive asthmatics [21]. Although, this work failed to highlight changes in the microbial community that were consistently associated with steroid-resistant asthma, the work did go on to define the influence of Haemophilus
    parainfluenzae on the expression of corticosteroid-regulated genes of BAL macrophages in an in vitro co-culture model. It concluded that co-culture with H. parainfluenzae as opposed to the commensal genus Prevotella resulted in inhibition of the steroid
    response. Another longitudinal study was conducted to measure the impact of the antibiotic azithromycin on the airway microbiota of five adult patients with asthma [22]. The result was the reduction in the representation of the Haemophilus, Pseudomonas,
    and Staphylococcus genera within the community, which coincided, with establishment of Anaerococcus as the most dominant members of the community.

    Despite limitations of small sample sizes, potential biases in sampling methods, and unanswered questions regarding treatment influence, the overall findings between most studies are generally consistent and provide further evidence that airway
    microbiota diversity associated with asthma is likely due to the disease itself (Figure 1). The other possibility is that the microbiome drives disease and/or features of the disease such as steroid non-responsiveness. Most importantly, now that these
    communities are being understood in greater detail, there is a pressing need to explore the mechanistic link between microbial communality and asthma development/severity, with research into the interaction between the microbiota and mucosal immunity
    being vitally important.

    Microorganisms involved in asthma airway colonization
    Download full-size image
    Figure 1. Microorganisms involved in asthma airway colonization. A cross-section of the human lower respiratory tract is depicted, showing sites of infection for different microorganisms and the effects that they have on airway function. The phylogenetic
    ring depicts the percentage abundance of bacterial phyla identified in various biological samples taken from the airways of asthma patients (Information used to compile figure was reported in [12,19]. Inner ring (bronchoscopic brushing samples); middle
    ring (BAL samples), and outer ring (induced sputum samples). Abbreviation: BAL, bronchoalveolar lavage.

    The potential contribution of airway microbiota to asthma subtypes and the immune response
    One of the classic features of asthma is the presence of specific immune cells in the airway. Simpson and colleagues [23] have used this to describe four inflammatory subtypes of asthma based on the immune cell profile of sputum taken from patients (
    Table 1). These subtypes include eosinophilic (eosinophils >3%), neutrophilic (neutrophils >61%), mixed granulocytic (increased eosinophils and neutrophils), and paucigranulocytic asthma (normal levels of both of these specific immune cell types).
    Numerous researchers and clinicians have used these asthma subtypes for classification. Recent work has begun to elucidate the association between lung microbiota function and immune response in eosinophilic and neutrophilic asthma subtypes that we
    describe below (Figure 2).

    Table 1. Asthma subtypes and molecular characteristics

    Asthma subtypes Molecular pathology
    Eosinophilic Eosinophils >3% in sputum taken from the airway

    Can be associated with high or low Th2

    Stimulation of IL-5 and other various cytokines

    Associated with steroid responsiveness

    Thickening of the basement membrane
    Neutrophilic Neutrophils >61% in sputum taken from the airway

    Can be associated with high Th17

    Stimulation of IL-8

    Associated with steroid non-responsiveness

    Normal basement membrane thickness

    Mixed-granulocytic Increased eosinophils and neutrophils, cytokine stimulation

    Paucigranulocytic

    Normal levels of eosinophils and neutrophils, cytokine stimulation
    Bacterial and viral infections of the airways activate immune and structural… Download full-size image
    Figure 2. Bacterial and viral infections of the airways activate immune and structural cells, promoting inflammation and influencing responses to other pathogens, allergens and pollution. The schematic depicts potential triggers and innate immune
    response of eosinophilic (Th2 dependent) and neutrophlic (non-Th2 dependent) asthma. Left panel: Environmental allergens such as pollen and mold spores can trigger Th2 asthma. Th2 immune processes begin with the development of Th2 cells and their
    production of the cytokines IL-4, IL-5, and IL-13. These cytokines stimulate allergic and eosinophilic inflammation as well as epithelial and smooth-muscle changes that contribute to asthma pathobiology. Right panel: Cigarette smoke, pollutants and the
    PAMPs from airway microbes including LPS from bacteria or ssRNA from respiratory viruses can potentially trigger non-Th2 asthma. There is a range of factors that can contribute to the development of non-Th2 asthma. These factors include infection-related
    elements, Th1 and Th17 immunity, non-Th2 associated smooth-muscle changes and the development of neutrophlic inflammation. Abbreviations: APC, antigen-presenting cell; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; dsRNA,
    double-stranded RNA; PGD2, prostaglandin D2. IFN, interferon; GRO, growth-regulated oncogene; IL, interleukin; LPS, lipopolysaccharide; PAMP, pathogen associated molecular pattern; ssRNA, single-stranded RNA; Th, T helper; TLR, Toll-like receptor.

    Eosinophilic asthma
    Eosinophil accumulation in the airway (eosinophilia) is associated with thickening of the basement membrane and is often responsive to corticosteroid treatment [24]. This eosinophilia is most commonly associated with allergic or atopic asthma and
    accounts for the majority of disease. The generally held view for allergic asthma is that it is driven by sensitization to an allergen that is followed by subsequent challenge. The result of this multifactorial event is the activation of T cells and the
    conversion to a T helper (Th)2 type immune response. Th2-associated cytokines IL-4, IL-5, IL-9, and IL-13 promote the presence of eosinophils in the airway and in turn lead to an increase in IgE levels in the blood. Additionally, IgE levels are known to
    be elevated in the respiratory tract of eosinophilic asthmatics in response to antigens from many common airway microbial colonizers [25]. IgE binds to IgE receptors on the surface of mast cells and becomes crosslinked upon binding of allergens resulting
    in mast cell degranulation. The result of mast cell degranulation is the release of preformed mediators of inflammation such as histamine, tumor necrosis factor (TNF)-α, IL-13, and IL-4. Ultimately, this results in enhanced vascular permeability and the
    recruitment of inflammatory cells to the airway. The link between Th2 responses and allergic inflammation was initially established in mice and subsequently Th2 cytokines were then detected in asthmatic patients. Transcripts of IL-4, IL-5, and IL-13 in
    patient sputum can be detected and quantified by PCR and can be used as biomarkers of a ‘Th2-high’ response [26]. Gene expression microarrays demonstrated that monitoring of CLCA1, periostin, and serpinB2 expression could be used as markers to
    estimate and monitor a Th2 response [27].

    Recent studies have begun to challenge the long held view that allergic reactions represent unintentional immune responses [28]. Instead it is proposed that allergic host defenses have evolved as protection against harmful substances such as irritants,
    noxious chemicals, and foreign toxins. The extent to which microbial derived products, toxins, or components present in the airway contribute to allergic responses remains a largely unexplored but exciting question. This suggests that the ability to
    cause tissue damage may be a common feature of substances that trigger appropriate allergic responses regardless of their source [28]. Little is known about the contribution of the airway microbiota to such mechanisms but clues are emerging that
    highlight the need for further investigation. For example, it is known that group 2 innate lymphoid cells (ILC2s) can be activated directly by microbes acting on Toll-like receptors (TLRs) [29,30]. Recent work in mice has led to the discovery that ILC2s
    can release Th2-type cytokines in response to epithelial damage and this may be a potential mechanism by which damage caused by members of the airway microbiota could elicit an asthmatic response [31–33].

    It has also been shown that low levels of microbe-derived lipopolysaccharide (LPS) sensed through TLR4 can enhance the Th2 response [34]; responses are context-dependent and LPS also induces Th1 responses. This again indicates that the airway microbiota
    has the potential to modulate the allergic response where different manifestations may be heavily dependent on the environmental context. Work with neonatal mice showed that manipulating the lung microbiota composition provided a potential protective
    role in allergic responses [35]. The work demonstrated that immediately after birth the airway mucosa was primed for a strong response to allergen challenge. However, 2 weeks postpartum the bacterial load in the lungs increased and there was a change in
    composition from Gammaproteobacteria and Firmicute dominance to the establishment of Bacteroidetes. This shift in community was associated with the inducement of the Helios T regulatory cell subset and decreased aeroallergen responsiveness. Future work
    should further elucidate the interaction between specific microbes and components of the immune system contributing to allergy.

    Neutrophilic asthma
    Neutrophils are one of the earliest immune cells recruited to sites of damage and infection of the airway. Many lung diseases such as COPD and CF are associated with neutrophilic inflammation [36,37]. Asthma is no exception with ∼30% of patients
    suffering from neutrophilic asthma. This is characterized by substantial and sustained increase in airway neutrophils (neutrophilia), which is linked to a poor response to inhaled corticosteroid treatment.


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