Phenotypic And Pathologic Definitions.

Introduction

Asthma, in 2006, was considered often as the monolithic entity. Therefore, in the time of the asthma diagnosis, it was considered to be appropriate in turning towards various guidelines, such as National Asthma Education and Prevention Program publications and the initiation of treatment on the basis of the degree of control or severity of the patient. The theme that is overreaching of this management of asthma is more than merely a mild intermittent disease. The treatment’s mainstay must be the ICSs (inhaled corticosteroids). The guidelines have been uniform that will be effective universally for all patients.

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What is asthma?

The pathologic or phenotypic definition seems to be an easier definition of asthma. According to the phenotypic definition, asthma consists of lung disease that is obstructive and whole reversibility after corticosteroids or bronchodilators are added in the concomitant bronchial hyperactivity setting. The asthma’s pathologic definition consists of eosinophilic bronchitis disease that have a characteristics of cytokine response robust type 2 (interleukin [IL] 13, IL-5, and IL-4) developing into a setting of an allergy (Al-Ramli et al., 2009). Hypersensitivity reactions play a harmful effect in the immune system. An immediate allergic reaction fall under Type I hypersensitivity reaction. Allergen specific T helper (Th) cells play an essential role in the pathogenesis of allergic hypersensitivity reactions. The Th cells stimulate complex immune reactions which generate the discharge of strong mediators and increases inflammatory cell’s recruitment. These in turn, induce an inflammatory response which directs to the allergic disease symptoms ( Kim et al., 2010).

Asthma Endotypes

A categorical diagnostic entity on the basis of distinct pathogenic pathway is being known as an endotype, a concept that is not idealized anywhere near realization (Moore et al., 2014). With such endotypes, there can be involvement of inherent and unique mechanisms (gene or genetic control pathways), mechanisms of extrinsic nature (environmental exposures, pathogens or viruses) or both interacting with each other.

Currently the most challenging and perplexing presentation of asthma is the noneosinophilic asthma. Its pathological definition is filled up with controversy. This asthma type, commonly, have the association with airway neutrophils and its increased prevalence. However, there are difficulties in separating the pathological findings that are inherent from the corticosteroids’ concomitant use and its confounding influence (Wenzel et al., 2013). These patients are regarded generally of having more severe presentation and generally more severe presentation inhaled corticosteroids of high dose or oral corticosteroids. The problems arises contrasting to the eosinophils’ effort with the inhibition of neutrophil (PMN [corticosteroids]) apoptosis by corticosteroids and therefore promoting their airway accumulation. Therefore, there are impediments in distinguishing the disease’s primary pathologic finding from the corticosteroid’s secondary influences. There are many studies that have argued that when there is withdrawal of inhaled corticosteroids before the performance of pathologic studies, it is revealed as to what is paucigranulocytic or nongranulocytic inflammatory process (Green et al., 2007).

Having consistency with the PMN cells’ putative role in noneosinophilic asthma, making the role of IL-17þ TH17 cells (T effector cells) has been proposed. With several mechanisms of IL-17, including granulocyte colony-stimulating factor’s induction, neutrophilic response of robust nature is produced. The mechanism that drives the expression of TH17 in asthma, having similarity with this disease, has been completely unknown. However, the studies advocate that in patients, expression of airway PMN cells is strongly associated with the asthma and concentration and presence of IL-17 (Nembrini et al., 2009).

Historically, all asthma has been regarded as eosinophilic. This term is inclusive of allergen-exacerbated asthma, sensitizing to atopy (inhaled aeroallergens), concomitant AR (allergic rhinitis), and exposure’s worsening symptoms. This phenotype has been more frequent in childhood-onset asthma (Xie and Wenzel, 2013).

The related phenotype consists of the individuals within whom eosinophils remains the main pathologic finding, although these individuals cease demonstrating idiopathic eosinophilic asthma or specific IgE sensitization. This phenotype may have the presence in any age, although its presence with adult onset asthma in particular among patient having more severe phenotype (Xie and Wenzel, 2013). The eosinophilic asthma’s another presentation consists of individuals having respiratory disease that is aspirin-exacerbated. Much like the case of idiopathic eosinophilic asthma, this phenotype has been mostly present in adulthood, and atopy cease to be an essential component. The features that are defining are inclusive of severe chronic rhinosinusitis with sensitivity and nasal polyps and other cyclooxygenase’s nonselective inhibitors (Steinke and Borish, 2015).

Therapeutic Implications

So far these asthma phenotypes that are crudely defined are suggestive of the central pathogenic mechanism and phenotype-specific therapeutic interventions (Table 1).

Global Railway versus Air

The extent of mediation of the neutrophilic asthma is by a high milieu IL-17, where the antagonists IL-17 must be effective therapeutics. This finding corroborated one clinical trial at least of a brodalimumab, anti IL-17 receptor antibody, in asthma. This antibody blocks IL-17 engagement and cytokine, IL-25, which is structurally related to the receptors (Busse et al., 2013). In enriching noneosinophilic individuals, the primary criteria of this study are to include where the inadequate control and its presence exists in spite of the inhaled corticosteroids’ regular use. It is unfortunate that the primary objectives of lung function and asthma control is not reached, albeit the retrospective analysis is suggestive of improvement in a cohort and with a baseline with high reversibility.

There have been several studies demonstrating the allergen avoidance benefits. However, the intriguing part is the aeroallergen avoidance related studies which demonstrate the lung function’s improvement, both sputum eosinophilia (airway inflammation) and AHR (airway hyperreactivity) persisted (table 2).

Global Railway versus Air

Additional to the immunotherapy and allergen avoidance is the allergen-exacerbated asthma’s therapeutic implication which has been IgE-targeting therapeutics usage, especially the omalizumab. US Food and Drug Administration has approved omalizumab based on its ability of inhibiting exacerbations of asthma inclusive of seasonal exacerbations of asthma that the rhinovirus infections drive (Teach et al., 2015).

Considering the IL-13 and IL-4’s essential role to drive the IgE isotype switch, the considerations would be obvious for their antagonists in allergen-exacerbated asthma patients. These cytokines’ antagonisms are seemingly logical with respect to their capacity of increasing adhesion and chemokines molecules’ expression, smoothing the muscle hypertrophy, enhancing bronchial hyperreactivity, and driving the goblet cell metaplasia to recruit inflammatory cells such as chemokines. The proteins’ distinct signature that these cytokines induces is identifiable and these cytokines, for IL-13, are inclusive of protein periostin. A secreted matrix protein is a periostin playing a key role in wound repair and tissue injury. The exposed epithelial cells in IL-13 contribute for transforming them to mesenchymal stem cells lacking cell-to-cell adhesion and polarity.

Therapeutics for Corticosteroids (Idiopathic Eosinophilic Asthma)

Corticosteroids are regarded as the therapeutic intervention that is most effective and the current asthma guidelines’ central recommendation. In the asthma, their efficacy provides reflection in major part of their ability in inducing eosinophil apoptosis. To the extent PMN apoptosis is inhibited by the corticosteroids in promoting their survival of long term, it has plausibility that asthma control can be worsened by these agents amongst the asthma patients not having eosinophilic phenotype (Corren et al., 2011). It is quite amazing that the reorganization of this concept took place as soon as the availability of corticosteroids is with asthma therapeutics.

Global Railway versus Air

Subsequently, the concept that is more compelling are the corticosteroids which may be ineffective was confirmed by Woodruff et al. (2009) in a study. The study had the involvement to collect from the asthma patients with bronchoscopic samples from those having withheld the inhaled corticosteroids and then performed the protein analyses. The identification of the 2 distinct cohorts by this approach of the asthma patients: TH2 low and TH2 high (type 2 cytokine signatures). Additionally, to the elevated IL-13 and IL-5 levels, the TH2-high cohort patients have been distinguished by the elevation of the IgE levels and BAL eosinophils and increased sputum. Contrastingly, the low cohort TH2 had the numbers of bronchoalveolar lavage eosinophil that cannot be distinguished from the health controls and therefore fits into paucigranulocytic or noneosinophilic phenotype. This study’s most important finding has been the phenotypic dichotomy’s effect responding to the inhaled corticosteroids’ subsequent addition. The TH2-high patients only had clinical improvement after inhaled corticosteroids are introduced (Fig 1).

Global Railway versus Air

The specifically targeting of the eosinophilic asthma in the newest approach involving antagonism of IL-5 reflects its role as eosinophil hematopoietin. The growth of the hematopoietic stem cells in the IL-5’s presence does differentiation of it in eosinophils’ pure populations and in the blockade or absence of IL-5 eosinophils has been prevented from the development. Additionally, IL-5 is a key factor of activation and survival for mature eosinophils. Therefore, to target the IL-5 has been the biotherapeutic agents’ inviting targets for asthma development. It is surprising that early studies could not succeed in revealing a benefit that is meaningful from those agents in spite of the achievement of their promise to eliminate the circulating eosinophils and bone marrow (Flood-Page et al., 2007). However, the studies conducted subsequently have realized the therapeutic approach’s potential. Retrospectively, and with consistency to focus on this article, the key requirement to identify the eosinophilia’s benefit was the enrollment study’s limitation to eosinophilic asthma patients. Therefore, in 2009, the
findings of 2 critical studies stated the anti IL-5’s benefits in asthma, but only when the limitation of the enrollment has been to sputum eosinophilia patients persisting in the corticosteroids’ presence (Haldar et al., 2009; Nair et al., 2009). In both these studies, a key finding has been the little influence of anti IL-5 on the symptoms of asthma, rescuing the use of bronchodilator or the lung function, acting primarily for the prevention of asthma exacerbations. This observation’s implication must be the IgE and allergen exposure, albeit central to exacerbations of asthma. After the establishment of the disease, the AHR and the asthma-associated inflammation persist. Independent of eosinophilia, in this case, may have meek influence on the daily degree of control or the asthma symptoms. As the induced sputum will be the basis of unacceptable determination for IL-5 blocking agents’ appropriateness, the studies that are more recent have led to the approval of US Food and Drug Administration for this modality instead had the focus on peripheral eosinophilia as adequate but flawed airway eosinophilia biomarker.

Asthma as an Epigenetic Tissue Modification Disease

Epigenetics essentially means the molecular processes modifying the chromatin and DNA in regulating the gene expression that is cell-specific. This is process underlying the differentiation of tissues. For instance, differentiation is driven by epigenetics of stem cells into cells of liver having the characteristics of liver gene signature. The DNA’s epigenetic modification and chromatin provides the explanation as to the way the preservation of the cellular differentiation taking place during cell division of lifelong in these liver cells. Thus, the explanations are provided by these processes as to the how the repackaging of DNA, at the time of cell division, into chromosomes when the hepatic differentiation’s memory is recalled by the subsequent daughter cells. The questions are raised by these findings as to whether asthma can be consisting of epigenetic modification in a similar state. The current studies are suggestive that there has been modification epigenetically by the airway epithelial cells so that the daughter cells and the epithelial cells and their daughter’s daughter cells can be retaining the capacity and adding infinitum in expressing the gene signature that is asthma-associated (Borish and Steinke, 2004) (Fig 2)

Global Railway versus Air

Pharmacologic Biotherapeutic Interventions and its Implications

This asthma concept as a disease is driven mainly by the epithelial cells that is epigenetically modified and has implications that is intriguing, especially for the clinical responses with regards to the earlier observations to biotherapeutic interventions. The interventions targeting the T and B effector cells’ adaptive immune responses, whether they are cytokine antagonism, IgE blockade, or allergen avoidance, better is done to prevent the asthma exacerbations compared to the prevention of the daily lung function, AHR, and asthma symptoms.

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Conclusion

The biotherapeutic agent that targets the mediators of downstream allergy, such as IL-13, IL-5, and IgE has been the molecular medicine’s exciting vindication. However, there must be targeting of the biotherapeutic agents to the phenotypes of individual asthma, and ideally to individual endotypes. The invitation of the biotherapeutic targets, in the near future, for the cytokine driven asthma of type 2 has been cytokines IL-33, IL-25, and TSLP that are epithelial derived. The generation of cytokines responding to the virus, allergen (airway injury) and then epigenetically programmed for remaining expressed constitutively by these epithelial cells of asthmatic airway. To target these epithelial-derived mediators that are epigenetically programmed instead of the adaptive immune system products may have the greater likelihood of improving daily asthma symptoms contrasting to the adaptive immune system’s targeting mediators.

References:

  • Al-Ramli, W., Prefontaine, D., Chouiali, F., et al. (2009) ‘T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma’, J Allergy Clin Immunol., 123: 1185-1187.
  • Borish, L. and Steinke, J. W. (2004) ‘Beyond transcription factors. Allergy’, Clin Immunol Int., 16:20-27.
  • Busse, W. W., Holgate, S., Kerwin, E., et al. (2013) ‘Randomized, double-blind, placebo controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma’, Am J Respir Crit Care Med., 188: 1294-1302.
  • Corren, J., Lemanske, R. F., Hanania, N. A., et al. (2011) ‘Lebrikizumab treatment in adults with asthma’, N Engl J Med., 365:1088-1098.
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  • Kim, H.Y., DeKruyff, R.H. and Umetsu, D.T. (2010) ‘The many paths to asthma: phenotype shaped by innate and adaptive immunity’, Nature Immunology, 11(7): 577‐584.
  • Moore, W. C., Hastie, A. T., Li, X., et al. (2014) ‘Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis’, J Allergy Clin Immunol., 133:1557-1563.
  • Nair, P., Pizzichini, M. M., Kjarsgaard, M., et al. (2009) ‘Mepolizumab for prednisonedependent asthma with sputum eosinophilia’, N Engl J Med., 360: 985-993.
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  • Steinke, J. W. and Borish, L. (2015) ‘Factors driving the aspirin exacerbated respiratory disease phenotype’, Am J Rhinol Allergy, 29:35-40.
  • Teach, S. J., Gill, M. A., Togias, A., et al. (2015) ‘Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations’, J Allergy Clin Immunol., 136:1476-1485.
  • Wenzel, S., Ford, L., Pearlman, D., et al. (2013) ‘Dupilumab in persistent asthma with elevated eosinophil levels’, N Engl J Med., 368:2455-2466.
  • Woodruff, P. G., Modrek, B., Choy, D. F., et al. (2009) ‘T-helper type 2-driven inflammation defines major subphenotypes of asthma’, Am J Respir Crit Care Med., 180: 388-395.
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