asthma pathophysiology essay

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Review article, pathophysiological mechanisms of asthma.

• Departments of Paediatrics and Paediatric Respiratory Medicine, Royal Brompton Harefield NHS Foundation Trust and Imperial College, London, United Kingdom

The recent Lancet commission has highlighted that “asthma” should be used to describe a clinical syndrome of wheeze, breathlessness, chest tightness, and sometimes cough. The next step is to deconstruct the airway into components of fixed and variable airflow obstruction, inflammation, infection and altered cough reflex, setting the airway disease in the context of extra-pulmonary co-morbidities and social and environmental factors. The emphasis is always on delineating treatable traits, including variable airflow obstruction caused by airway smooth muscle constriction (treated with short- and long-acting β-2 agonists), eosinophilic airway inflammation (treated with inhaled corticosteroids) and chronic bacterial infection (treated with antibiotics with benefit if it is driving the disease). It is also important not to over-treat the untreatable, such as fixed airflow obstruction. These can all be determined using simple, non-invasive tests such as spirometry before and after acute administration of a bronchodilator (reversible airflow obstruction); peripheral blood eosinophil count, induced sputum, exhaled nitric oxide (airway eosinophilia); and sputum or cough swab culture (bacterial infection). Additionally, the pathophysiology of risk domains must be considered: these are risk of an asthma attack, risk of poor airway growth, and in pre-school children, risk of progression to eosinophilic school age asthma. Phenotyping the airway will allow more precise diagnosis and targeted treatment, but it is important to move to endotypes, especially in the era of increasing numbers of biologicals. Advances in -omics technology allow delineation of pathways, which will be particularly important in TH2 low eosinophilic asthma, and also pauci-inflammatory disease. It is very important to appreciate the difficulties of cluster analysis; a patient may have eosinophilic airway disease because of a steroid resistant endotype, because of non-adherence to basic treatment, and a surge in environmental allergen burden. Sophisticated –omics approaches will be reviewed in this manuscript, but currently they are not being used in clinical practice. However, even while they are being evaluated, management of the asthmas can and should be improved by considering the pathophysiologies of the different airway diseases lumped under that umbrella term, using simple, non-invasive tests which are readily available, and treating accordingly.

Introduction: Approaching Airways Disease

The recent Lancet Asthma Commission ( 1 ) was predicated on the assumption that the term “asthma” was no more a diagnosis than is “arthritis” or “anemia.” It is an umbrella term that should be used to describe a constellation of clinical symptoms, namely wheeze, breathlessness, chest tightness and cough, and should be followed by the question “what sort of asthma is this?” Dissecting out the individual asthmas is increasingly important as novel biologicals with different modes of action are increasingly being deployed. The ultimate aim is to discover endotypes of asthma, but currently we have not yet got to this point. The importance of endotyping is illustrated by the extraordinary achievements when the endotypes and the gene-class specific sub-endotypes of cystic fibrosis (CF) were first separated from the generality of conditions with chronic airflow infection and inflammation. The result has been the specific, molecular therapies ( 2 – 4 ), none of which would have come to the bedside if they had been tested on every child with a chronic wet cough. It is also important, but largely outside the scope of this chapter, to set airway disease in the context of extra-pulmonary co-morbidities such as obesity, and environmental and lifestyle factors, such as adverse environmental exposures and adherence ( 5 ).

The conventional view of at least school age and adult asthma is that the root cause is airway inflammation, which leads to airway hyper-responsiveness, and, secondary to repeated episodes of inflammation, airway remodeling. However, a critical review of the evidence shows that this view is untenable. There is only a weak correlation at baseline between eosinophilic inflammation and bronchial hyper-responsiveness ( 6 , 7 ). The anti-IgE monoclonal omalizumab reduces airway eosinophilia, but has no effect on bronchial hyper-responsiveness ( 8 ), whereas the anti-TNF monoclonal etanercept reduces hyper-responsiveness but has no effect on airway inflammation ( 9 ). Furthermore, there is no relationship between the extent of airway remodeling, specifically reticular basement membrane thickness, and the degree or duration of any inflammatory parameter ( 10 ). Indeed, there is evidence that remodeling may be protective under some circumstances, discussed in more detail below. Thus, the relationships between the three classic components of asthma are more complex than previously thought, and this is highly relevant to considerations of pathophysiology.

First Principle: Deconstructing Airway Disease

Adverse stimuli can affect any biological tube in relatively limited and stereotypical ways. These are:

• Narrowing to cause fixed obstruction

• Narrowing to cause variable obstruction which changes spontaneously over time, and with treatment

• Inflammation with various cell types predominant; inflammation may be harmful or beneficial

• The tube may become infected with combinations of bacterial, viral and fungal pathogens

• There may be increased “twitchiness” of the tube—this is different from variable obstruction. An increased reflex expulsive effort (cough) may not be accompanied by transient airflow obstruction

• The tube contents may be abnormal: including being too wet, too many solids, or too dry.

Furthermore, there are domains of risk, which also need to be considered in any discussion of pathophysiology:

• Risk of acute asthma attacks, which may be fatal

• Risk of impaired trajectories of lung growth, which may sometimes but not inevitably be associated with asthma attacks

• (in pre-school children) risk of progressing from episodic wheeze to eosinophilic atopic school age asthma

• A fourth risk, about which little is known and will not be discussed here, is the risk of failing to remit

Clearly not all are relevant to all pediatric airways diseases: the hallmark of CF is the effects of the airway being too dry [“low volume hypothesis” ( 11 )] and infection and neutrophilic inflammation, whereas some at least of the asthmas are dominated by eosinophilic airway inflammation. What is also clear is that we need modern–omics or genetic tools to try to dissect out these components—and these are sadly lacking. Indeed, currently we are not even trying routinely to identify treatable traits in airway disease, instead haphazardly making diagnoses and embarking on therapeutic trials without making simple measurements in order objectively to phenotype the airway disease. The three important treatable traits, which will be considered in turn, are:

• Does the child have the treatable trait of eosinophilic airway inflammation which is likely to respond to inhaled corticosteroids (ICS)?

• Does the child have the treatable trait of (usually short-acting, β-2 agonist sensitive) reversible airflow obstruction? And conversely, does the child have the untreatable trait, meaning treatment should be discontinued, of fixed airflow obstruction?

• Does the child have the treatable trait of bacterial infection which is driving the disease and can be treated with antibiotics?

The contention of this chapter is that the isolated questions “does my child have asthma?” and (for example) “do survivors of preterm birth have a higher risk of asthma?” are meaningless in isolation. The correct questions are “does this child have an airway disease at all, or are the symptoms in fact due to deconditioning or some other cause ( 12 )?” and, if the child has an airway disease, “what is the nature of this particular airway disease?”

Current Best Practice: Phenotyping the Airway

A phenotype is defined as the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment. It is important to make the distinction between phenotyping which is of clinical value (changes treatment, prognostic value) from those determining mechanistic pathways. However, if phenotyping does not help in either domain, it cannot be said to be useful. An endotype is defined as a subtype of a condition, which is defined by a distinct functional or pathobiological mechanism. In general, phenotyping leads to rather non-specific treatment, whereas endotyping opens up an exciting vista of pathway specific therapies, as I will show.

Airway Inflammation, and the Potentially Treatable Trait of Airway Eosinophilia

Airway eosinophilia.

ICS are amongst the most effective agents in the whole of therapeutics for the vast majority of children with eosinophilic asthma. Low dose treatment, if taken efficiently and regularly, will result in complete control of asthma in most children ( 13 ), while accepting there are steroid resistant phenotypes. The most direct evidence of airway eosinophilia is of course obtained at fibreoptic bronchoscopy (FOB) with broncho-alveolar lavage (BAL) and endobronchial biopsy. This is of course not ethical or practical in most children, and non-invasive methods must be used. Induced sputum was initially the most popular technique, and although this is time-consuming, it is perfectly feasible as a diagnostic test for infection even in resource poor areas ( 14 ). Although in older children sputum and BAL eosinophilia are tightly correlated ( 15 ), this is not the case in pre-schoolers ( 16 ). Furthermore, there is a failure rate of up to 20% ( 17 ), and induced sputum does not reflect mucosal inflammation.

Of the other non-invasive methods, peripheral blood eosinophil count has become most popular. It reflects BAL eosinophilia ( 15 , 18 ), and, even more importantly, is an excellent biomarker predicting response to anti-TH2 monoclonal antibody strategies ( 19 – 21 ). Peripheral blood eosinophil count can be measured on a finger prick sample with point of care equipment ( 22 ). Significantly, in the first attempt at personalized medicine in pre-school children, the combination of a peripheral blood eosinophil count >300/μλ and aeroallergen sensitization was the strongest predictor of response to ICS ( 23 ). Exhaled nitric oxide (FeNO) has also been used as a surrogate for airway eosinophilia. The utility of this method in reducing asthma attacks has been demonstrated ( 24 ), but although there is a relationship with induced sputum eosinophil count, it varies between individuals and is inconsistent in the same individual over time ( 25 ). Clearly FeNO and induced sputum are complimentary and useful, but exactly how they should be used in combination is unclear.

However, the presence of airway eosinophils should prompt critical thought. Firstly, airway eosinophilia, although often related to Type 2 inflammation, is not synonymous with that endotype, and this needs to be borne in mind when contemplating anti-TH2 monoclonal therapies. In our cohort of severe, therapy resistant asthmatics, those with steroid resistant airway eosinophilia had very little evidence of ongoing secretion of the signature TH2 cytokines interleukin (IL)-4, IL-5 and IL-13, in either induced sputum supernatant, BAL or immunohistochemistry of endobronchial biopsy ( 26 ). Also, the U-BIOPRED group, using sputum transcriptomics in adult asthmatics documented a group which included patients with moderate sputum eosinophilia, who instead of having the expected TH2 handprint, were characterized by genes of metabolic pathways, ubiquitination and mitochondrial function, as well as, in another study, an IL-6 modulated pathway (below).

Furthermore, if eosinophils are present in the airway, their role or otherwise in disease causation should be carefully considered. In adults at least, eosinophilic bronchitis is a cause of chronic cough, but with no evidence of reversible airflow obstruction; treatment is with ICS, but not β-2 agonists ( 27 ). In a challenging study, airway biopsies were compared in patients with active asthma, normal controls, and patients who by any criteria had outgrown their previously diagnosed asthma ( 28 ). The airway wall histology, in terms of eosinophilia and reticular basement membrane thickness was the same irrespective of whether the patient had active asthma or had “outgrown” the disease. This leads to the challenging question as to what is the “X-factor” that is needed to convert airway eosinophilia into airway disease? At the moment this remains completely unknown.

Having said all this, clearly if there is no airway eosinophilia, it seems to make little sense to prescribe an anti-eosinophil strategy such as ICS. Although it is true that corticosteroids have numerous genomic and non-genomic effects ( 29 ) which hypothetically could be beneficial in airway disease, this has never been shown, and there may be potentially adverse effects in at least some airway diseases, for example reducing neutrophil apoptosis and prolonging the survival of this cell in the airway ( 30 ). Surely in the twenty-first century we should not prescribe anti-eosinophilic medications if there is no airway eosinophilia to treat, any more than anti-hypertensives should be prescribed to people who have a normal blood pressure?

Neutrophilic Asthma?

This is another area which illustrates the danger of extrapolating adult studies to children. Asthma characterized by mucosal and sputum neutrophilia is well described in adults ( 31 ), who tend also to have severe asthma with less evidence of atopy. Unsurprisingly, neutrophilic asthma is steroid non-responsive. By contrast, in our cohort of children with severe asthma, multiple atopic sensitization was common, but there was no evidence of mucosal, sputum or BAL neutrophilia ( 26 ). However, in a subgroup of patients neutrophils were found within the epithelium ( 32 ), and, quite unlike what might be expected from adult data, these patient had better symptom control (Asthma control test, ACT) and better first second forced expired volume (FEV 1 ) while being prescribed a lower dose of ICS. Although it is always dangerous to move from cross-sectional associations to hypotheses, nonetheless it would seem that, whatever the role of neutrophils in adult asthma, in pediatric asthma neutrophils are having a beneficial effect. This raises the intriguing possibility that bacterial infection may have a role in some pediatric asthmas. Again highly speculatively, is it possible that excessively high doses of ICS might actually worsen “bacterial asthma” (if it exists!) by causing topical mucosal immunosuppression ( 33 ), leading to a positive feedback loop of worsening symptoms leading to higher ICS doses leading to worsening symptoms? Further data are needed to explore this. However, a practical clinical message is that the finding of BAL or mucosal neutrophilia should prompt a search for another diagnosis.

Fixed and Variable Airflow Obstruction

Variable airflow obstruction.

Wheeze is a frequently sought, and often misinterpreted sound. Even when a polyphonic, musical predominantly expiratory noise is heard by the physician, all it betokens is narrowing of the airway lumen. It is not synonymous with airway smooth muscle constriction. Causes include intraluminal airway secretions; airway malacia which may be localized or generalized; and extraluminal compression, for example by a mass of lymph nodes. Most of the asthmas as defined above have the hallmark of either or both of obstructive physiology which improves with acute administration of a short acting β-2 agonist, or normal physiology but with an exaggerated response to stimuli such as cold air or allergen challenge.

In terms of variable airflow obstruction, as a profession we have been remiss in failing to document this objectively. Even pre-school children can perform spirometry, and criteria for adequate curves ( 34 ) and definitions of bronchodilator responsiveness ( 35 ) for this age group have been published. Simple field tests, like acute response to a short acting β-2 agonist, a short period of home peak flow or increasingly electronic spirometry monitoring, and an exercise challenge may be informative. Although there is no one definitive diagnostic test for asthma, and all the above have a high specificity but low sensitivity for asthma ( 36 ), the more tests that fail to demonstrated variable airflow obstruction, the less likely is the treatable trait of bronchodilator responsive airflow obstruction to be present.

AHR correlates poorly with inflammation (above), but of course there is a relationship which is best described by a two-component model, “inflammatory” and “anatomical.” Three major longitudinal studies ( 37 – 39 ) have measured AHR very early in life, before any significant exposure to infection or allergen, and certainly before there is any evidence of airway inflammation or remodeling ( 40 ). Each has shown a strong association between early AHR and adverse long term respiratory outcomes. The likely pathological basis is increased airway length and reduced radius, leading to a baseline increase in airway resistance ( 41 ), which with further narrowing by a constrictor stimulus leads to an exaggerated reduction in airflow. There is also evidence in later life that airway inflammation causes a component of AHR, and that anti-inflammatory therapies can improve AHR ( 42 ).

In terms of the practical value of measuring AHR in the clinic, population studies have shown that, although in group data, AHR relates to asthma severity, many normal people can be shown to have AHR but have no symptoms ( 43 ). Thus, “abnormal” AHR of itself does not lead to disease; by analogy with the airway eosinophil story, what is the “X-factor” that converts asymptomatic AHR to an airway disease? Again, this is completely unknown. However, what is certain is that failure to demonstrate AHR in a patient said to be symptomatic with asthma should lead to reconsideration of the diagnosis; certainly, if a child is thought to have eosinophilic airway inflammation but AHR cannot be demonstrated, then the child's symptoms are not due to eosinophilic asthma.

Fixed Airflow Obstruction

The importance of this untreatable trait is that ICS and other therapies should not be escalated when there is no hope of benefit. There is no generally accepted pediatric definition of fixed airflow obstruction. In general, it should be defined as an abnormal FEV 1 (more than 1.96 Z-scores below normal) after a systemic corticosteroid trial and the acute administration of short-acting β-2 agonist, but neither the dose, duration or route of administration of systemic steroids, nor the dose of short-acting β-2 agonist is agreed. We use a single injection of intramuscular triamcinolone (40 mg in a child weighing <40 kgm, 80 mgm in the rest) to ensure adherence, and 1 mgm of salbutamol via a spacer ( 44 ). We found very little evidence of benefit from adding extra doses of triamcinolone ( 45 ). It should be noted that the measurement of steroid responsiveness in children with asthma encompasses more than just measuring spirometry; we use a multi-domain approach ( 46 , 47 ).

One component of airway obstruction is determined antenatally. Maternal nicotine exposure (active and passive smoking, vaping) has been shown in animal models and humans to lead to structural changes with a readout of airflow obstruction shortly after birth, before the first viral infection ( 41 , 48 – 52 ). Other adverse factors include maternal exposure to environmental pollution ( 53 ), maternal hypertension ( 54 ), and any factor leading to a low birth weight or prematurity or both ( 55 , 56 ). The second component is the structural airway wall changes in established asthma, including increased airway smooth muscle, reticular basement membrane thickening, increased numbers of goblet cells and increased airway vascularity. Conventionally, these are considered to result from cycles of airway inflammation and contribute to airflow obstruction (above). However, at least in pediatrics, most studies linking inflammation and remodeling are cross-sectional and observational, and demonstrating association is a long step from proving causation. It is currently not possible to synthesis a coherent account of the pathophysiology of remodeling, and one can only present a few statements which require integration and explanation.

1. At least some aspects of remodeling, for example increased reticular basement membrane thickening, plateau in childhood, and are non-progressive into adult life ( 10 ).

2. No pediatric studies have shown eosinophilic airway inflammation with no evidence of remodeling. Remodeling has been described in the absence of current airway eosinophilia, but these children have been prescribed usually high dose ICS, and these data are equally consistent with the hypothesis of ICS having successfully treated airway eosinophilia as the alternative, that remodeling precedes airway eosinophilia ( 57 ).

3. Although airway remodeling can be partially attenuated by prolonged use of high-dose ICS ( 58 , 59 ), the changes are much more steroid resistant than is airway eosinophilia.

4. Reticular basement thickening is inversely correlated with AHR, ( 60 ) and thus may be a protective response of the airway, protecting against life-threatening bronchoconstriction.

5. It is at least conceivable that reticular basement membrane thickening is a protective measure designed to limit penetration of cytokines and chemokines into the systemic circulation, and possibly also protect the airway mucosa from tissue damaging enzymes within the lumen ( 61 ).

6. On the other hand, the increase in airway smooth muscle in asthma ( 62 ), and the beneficial responses seen in adults with bronchial thermoplasty together with reduction in smooth muscle in animals submitted to thermoplasty ( 63 , 64 ), suggests this aspect of remodeling is adverse.

Airway Infection and the Asthmas

This is another area that is currently difficult to understand. Some issues are clear; acute attacks of wheeze are usually precipitated by respiratory viral infections at all ages ( 65 ). Recent studies have shown that bacteria are isolated equally frequently during a wheeze attack ( 66 ), but it is unclear whether bacteria cause the attack, or are the result of a transient mucosal immunoparesis secondary to viral infection or iatrogenic as a result of ICS treatment ( 33 ). The general failure of antibiotics to impact acute wheeze attacks to any great degree is a strong pointer against a causal role for bacteria. We also know that the airway microbiome differs between normal and asthmatic children ( 67 ), and that airway neutrophilia in children appears to be beneficial rather than the reverse ( 32 ), implying a more important role of infection than previously thought. It is also clear that very early nasopharyngeal bacterial colonization with bacteria is associated with a mixed TH1/TH2/TH17 mucosal response, and subsequent adverse respiratory outcomes ( 68 – 72 ), although whether bacterial colonization is causal, or a marker of a subtle immune deficiency, is unclear. In a study using bronchoscopy and BAL to measure airway inflammation and infection, and the airway microbiota, in severe pre-school wheezers, we demonstrated two separate microbiota-based clusters; a Moraxella positive, airway neutrophilic group, and a mixed microbiota, macrophage and lymphocyte predominant group ( 73 ). Interestingly, these did not relate to clinical phenotype or markers of atopic status. Long term follow up will be needed to determine the significance of these clusters. There are some in vitro data lending plausibility to a link between bacterial infection and airway eosinophilia; in a nasal polyp model, Staph aureus binds via TLR2 leading to epithelial release of the alarmins TSLP and IL33, and the TH2 signature cytokines IL5 and IL13 ( 74 ). However, we need more data about the role of bacteria and the interactions with airway eosinophilia to try to understand asthma pathophysiology.

Of more immediate practical clinical significance is the need to determine whether the child with respiratory symptoms has an underlying chronic bacterial infection which will respond to oral antibiotics [“persistent bacterial bronchitis (PBB)”] ( 75 , 76 ). Typically the symptoms are of wet cough not wheeze, but secretions narrowing the lumen may cause wheeze, and non-wheeze noises may be misinterpreted by the family. For most of these children, invasive sampling is not appropriate. We have shown that the yield of organisms is much greater with induced sputum, even in young children, compared to cough swabs, and indeed induced sputum results are comparable to FOB ( 16 ). It should be noted that PBB, like bronchiectasis, is a description not a diagnosis, and should prompt a focused diagnostic work-up ( 77 ).

The Time Domain: Often Unappreciated

The two important pathophysiological areas are firstly, the stability of measurements over time, and secondly, the extent to which sophisticated analysis of simple measurements over a long time period can help us understand asthma pathophysiology and understand risk.

Temporal Stability of Measurements

Adult studies in which sputum cell counts are used to guide treatment have given promising results, in particular in the reduction of asthma attack frequency ( 78 ). When we attempted to replicate this study in pediatric asthma ( 79 ), we actually found that sputum cellular phenotypes were very variable in the same individual over time, in both severe and mild-moderate asthma ( 80 ). These discrepancies are unexplained, but underscore the importance of not critically extrapolating from adults to children. Likely sputum cell counts reflect not merely the underlying disease, but environmental factors and treatment adherence. The U-BIOPRED group used breath-omics (the eNose) to define three clusters, but also noted that many patients changed cluster as peripheral blood eosinophil count changed over time ( 81 ). Cluster stability is discussed in more detail below.

Fluctuation Analyses

The first major paper used time series analyses of fluctuations in peak flow to develop a quantitative basis for objective risk prediction of acute asthma attacks and for evaluating treatment effectiveness ( 82 ). Subsequent manuscripts from this group confirmed that by considering measurements of peak flow and spirometry in isolation, rather than as part of a series, resulted in important information being lost. These and other mathematical techniques could be used to predict the response to β-2 agonists ( 83 ) and whether ICS withdrawal was likely to be successful ( 84 ). Furthermore, the method distinguished between asthma and healthy controls, partly independent of atopy, and inflammation but related to the 17q21 locus ( 85 ). These mathematical techniques have not found their way into the routine asthma clinic, but clearly this sort of mathematical analysis is giving potentially important information about asthma pathophysiology which may aid management.

Summary: What Is Current Best Practice?

The days of diagnosing and treating asthma without making objective measurements are past. Is there any other chronic condition in which simple tests are available, but are routinely not performed before committing a child to long term treatment? We should use our knowledge of the pathophysiology of asthma to phenotype the airway, even in young children, focusing on the treatable traits. It is out with the scope of this article, but we should also consider any extra-pulmonary co-morbidities and social and environmental factors when planning management.

Special “Asthmas”: How Does the Lancet Commission Help us?

Most of the phenotyping issues arise in children who solely have an airway disease. However, there are some situations in which airway phenotyping is helpful in understanding pathophysiology and planning treatment.

Pre-school Wheeze: Is It Asthma, Dr?

As discussed, this question is without meaning, as is the statement that asthma cannot be diagnosed until a given and entirely arbitrary age. The proper approach is to determine which (if any) treatable traits the infant exhibits. The INFANT study ( 23 ) was discussed above; so at the very least, rather than asking pointless questions or making fatuous statements, a blood eosinophil count should be performed and aeroallergen sensitization determined. Ideally spirometry should be measured, but at the very least, if the child becomes acutely wheezy, this should be documented by a physician, and the response of wheeze intensity and oxygen saturation to inhaled β-2 agonist determined. If airway infection and PBB is suspected, documentation with cough swab or induced sputum that there is actually infection present should be mandatory, especially if multiple or prolonged antibiotic courses are being used.

Wheeze in the First Year of Life: What Is It, Dr?

Very little is known about this asthma. We know it is not related to airway eosinophilia ( 40 ), so ICS should not be prescribed. We know it is common, and the prevalence across the world is highly variable ( 86 ). This is an area where a lot more work is needed on pathophysiology.

Does the Child With Another Pulmonary or a Systemic Disease Also Have Asthma?

Very frequently, ICS are prescribed to children with reasons other than asthma for being symptomatic, often either preceding the realization that a non-asthma disease is present, or on the “just in case” principle. This is to be deplored; ICS have potential serious adverse events, not least the increased risk of pneumonia ( 87 ), tuberculous ( 88 ) and non-tuberculous Mycobacterial infection ( 89 ), at least from adult studies.

“Asthma” in Other Pulmonary Diseases

The classical quandary is whether survivors of premature birth have “asthma” ( 90 ). Again, phenotyping resolves this. It is clear from a number of studies that these children have fixed and variable airflow obstruction ( 91 , 92 ). However, FeNO is normal not raised, even in the absence of ICS ( 93 ), nor is there an elevation of exhaled breath temperature ( 94 ), a non-specific sign of inflammation (“calor” in the parlance of yesteryear). Thus, unless there is evidence in a given individual of a second diagnosis of atopic, allergic asthma (raised FeNO and peripheral blood eosinophil count, aeroallergen sensitization), ICS should not be prescribed. The same principles of investigation apply to other airway diseases, such as obliterative bronchiolitis and the airway disease after neuroendocrine cell hyperplasia of infancy; these are discussed in detail elsewhere ( 95 ).

“Asthma” in Children With a Systemic Disease

Exemplar diseases are CF, primary ciliary dyskinesia (PCD) and sickle cell anemia (SCD). We have shown that the prescription of ICS in PCD is haphazard and bears no relationship to any marker of atopic sensitization or airway eosinophilia ( 96 ). In both CF and PCD, where there is evidence that airway neutrophilia leads to tissue damage from the release of proteases and other enzymes, inhibiting neutrophil apoptosis with ICS (above) may have particularly adverse consequences. In these situations also, determining the presence or otherwise of the treatable traits airway eosinophilia and β-2 responsive bronchoconstriction should be used to determine treatment. SCD is a particularly interesting airway disease. Compared with controls, SCD children had fixed but not variable airflow obstruction, and no evidence of AHR or airway eosinophilia ( 97 ) we speculate that the airway disease may be on the basis of airway ischaemia due to microinfarcts secondary to sickling, analogous to what is seen more dramatically when the bronchial arteries are stripped off the airway during the unifocalisation procedure ( 98 ). So in all systemic conditions, if a treatable trait is present it should be treated, but treatment for a non-existent problem should be withheld.

Obesity Asthma—Not Lean Asthma in a Fat Body

The impact of the obesity epidemic across the world is well known, and the question as to whether obesity “causes” asthma is hotly debated ( 99 ). Again, phenotyping and looking at pathophysiology sheds light on the subject. The first question in a child who is breathless and obese is, does the child have an airway disease at all? Even in lean children, exertional breathlessness is more often due to deconditioning than asthma or exercise-induced laryngeal obstruction (EILO), and many non-asthmatics were treated with inhaled medication ( 12 ). A cardiopulmonary exercise test with measurements of any post-exercise bronchoconstriction may be informative.

If the obese child truly has an airway disease, then its nature should be characterized. Of course, obesity does not prevent the development of atopy, and the child may have standard atopic, eosinophilic pediatric asthma. However, obese asthma may be relatively ICS resistant, suggestive of another phenotype in some cases. Dysanaptic airway growth is defined as a normal FEV 1 with a greater than normal FVC, and thus a reduced FEV 1 /FVC ratio ( 100 ). Essentially airways are of normal caliber but increased length, the latter thought to be determined by lung size. In a study of six adult cohorts, four with longitudinal data, dysanapsis was found to be commoner in the obese, and associated with worse outcomes including severe asthma attacks and use of oral prednisolone. Studies on whether obese asthma is associated with Type 2 inflammation are conflicting ( 101 , 102 ). It is well known that obesity is a pro-inflammatory condition. There are intriguing data suggesting that the airway may be the target of systemic inflammation, instead of the source of inflammatory cytokines spilling into the systemic circulation. In a study of two adult cohorts, plasma IL-6 was measured as a marker of systemic inflammation and related to BMI and asthma outcomes ( 103 ) Patients who were IL-6 high were more likely (but not inevitably) obese, and had worse FEV 1 and more likely a history of asthma attacks. There was no relationship between IL-6 and serum IgE or sputum eosinophils, demonstrating that the effects of systemic inflammation were not mediated via Type 2 inflammation. Again these studies indicate the need to go back to pathophysiology, and the utility of airway phenotyping when considering airway disease, especially if it is non-responsive to conventional therapy.

The Pathophysiology of Asthma Risk

Increasingly the importance of future risk as a domain to be considered in asthma management 1 . If risk is to be managed, it must be measured, and the underlying pathophysiology of the risk be understood.

Asthma Attacks

Asthma attacks are all too common, may cause death, impair quality of life, incur a huge burden of health care cost and are associated with worsening respiratory and lung growth trajectories. Asthma attacks are not “exacerbations,” a futile word implying a reversible inconvenience ( 104 , 105 ); they are lung attacks. A recent meta-analysis of the risk factors for an asthma lung attack ( 106 ), as did the UK National Review of Asthma Deaths 2 , highlighted that having had one bad attack, the patient was at high risk of having another. Many asthma fatalities related to social factors, such as poor adherence and failure to engage with regular follow up reviews. However, the underlying pathophysiology of asthma attacks is also important. Specifically, the concept that asthma control may be good, but risk of a future attack high, is pivotal.

Asthma attacks may be driven purely by respiratory viral infection, with no background Type 2 inflammation, usually in pre-school children with episodic viral wheeze ( 107 ). A huge surge in environmental allergen burden in the absence of viral infection may also rarely cause acute asthma attacks, as in the Barcelona soya bean epidemics ( 108 ), and thunderstorm asthma ( 109 ). The vast majority of attacks are respiratory viral driven in patients who have background ongoing type 2 inflammation; thus the combination of respiratory viral infection, allergic sensitization and allergen exposure was very strongly predictive of an asthma attack ( 110 ). It has been shown that using FeNO and (in adults) induced sputum eosinophil count to titrate ICS treatment leads to a reduction in asthma attacks ( 24 ). Inadequate ICS treatment (usually related to non-adherence) was another strong predictor of an asthma attack ( 106 ). Omalizumab therapy in the summer given to children on step 5 therapy who had had an asthma attack in the previous year ameliorated the autumnal rise in asthma attacks driven by returning to school and winter viral infections ( 111 ). Finally, in a proof of concept, double blind, randomized controlled study, mite impermeable bedding led to a reduction in oral corticosteroid use in the year after an asthma attack in children sensitized to house dust mite ( 112 ). This allows a risk prediction index for asthma attacks ( 112 ). The Seasonal Asthma Exacerbation Prediction Index (SAEPI) has been validated as a means of predicting children at risk for an asthma attack ( 113 , 114 ). For those aeroallergen sensitized, an attack in the prior season and reduced spirometry predict a further asthma attack irrespective of season. Measures such as increased numbers of positive allergen skin prick tests, high prescribed ICS doses, increased FeNO, blood eosinophil counts and total and specific IgE levels may predict a seasonal asthma exacerbation. In summary, uncontrolled Type 2 inflammation, even in the face of good asthma symptom control, is a major risk factor for future asthma attacks.

There are other factors of importance which have been reviewed elsewhere ( 115 ). There are some asthma patients who never have an attack, implying either genetic protection or susceptibility factors, which are poorly understood. One example is the gene for the epithelial protein CDHR3, which is the receptor for RV-C ( 116 ), and gene mutations may convey increased susceptibility to attacks ( 117 , 118 ). Indoor and outdoor air pollution, including tobacco, and vitamin D deficiency potentially through multiple immunological and other pathways ( 119 ), are all associated with increased risk of asthma attacks.

Interestingly, many severe asthma patients never have an attack, for reasons which are unclear. Analysis of the SARP-3 cohort showed that nearly half never had an asthma attack, but a quarter had at least three attacks per year ( 120 ). Peripheral blood eosinophil count, body mass index, and bronchodilator responsiveness were positively associated with frequency of attacks, but not asthma duration, age, sex, race, and socioeconomic status. The findings were replicated in previous SARP patient cohorts.

Adverse Trajectories of Lung Function

There is an extensive literature on tracking of lung function, from a series of overlapping birth cohorts ( 121 ). Although there are discrepancies, some due to methodological issues such as lung function measurements in infancy, the balance of the evidence is that spirometry tracks from the pre-school years to late middle age at least, with possible deviations from tracking if puberty is late with a subsequent fast growth trajectory ( 122 ). In summary, spirometry rises to a plateau at about 20–25 years of age and thereafter declines ( 123 ). Adult studies have shown that failure to reach a normal spirometric plateau carries a 26% risk of COPD, compared with a 6% risk in those who attain their full growth potential (and who develop COPD because of an abnormally rapid rate of decline of spirometry) ( 124 ). A number of cohort studies have shown that some children have persistently low spirometry during childhood, putting them in the high risk category. The pathophysiology of this phenotype is poorly understood ( 125 – 127 ). The Tucson group used latent class analysis to determine that there were two trajectories, normal, and low lung function. Risk factors for the low lung function group included a history of maternal asthma (20.0 vs. 9.9%; P = 0.02); early life RSV lower respiratory tract infection (41.2 vs. 21.4%; P = 0.001); and physician-diagnosed active asthma (whatever the value of that label) at age 32 years (43.9 vs. 16.2%; P < 0.001) ( 125 ). In the Tasmanian cohort ( 126 ), there were three low trajectories (early below average, accelerated decline; persistently low; and below average); predictors included childhood asthma, bronchitis, pneumonia, allergic rhinitis, eczema, parental asthma, and maternal smoking. This group were followed up into the sixth decade, and COPD risk could be calculated. Odds ratios were 35·0, 95% CI 19·5-64·0 (early below average, accelerated decline): 9·5, 4·5–20·6 (persistently low); and 3·7, 1·9–6·9 (below average). In a combined analysis of the MAAS and ALSPAC cohorts ( 127 ), the persistently low trajectory was associated with severe wheeze attacks, early allergic sensitization, and tobacco smoke exposure. However, although it is clear that there is a group of asthmatics with low trajectory lung function who are at risk of COPD, it is not clear that anything can be done to reverse this. The Tasmanian group showed that risks were exacerbated in those children who went on to smoke, and certainly general advice should be given about risk avoidance; but this is clearly an area of asthma pathophysiology which merits further work. Also of note, and meriting further work is the association of high early all-cause mortality in populations with impaired spirometry ( 128 , 129 ); it may well be that low spirometry should be used as an important signal of systemic disease ( 130 ).

Risk of Progressive Disease

Many if not all children who develop atopic eosinophilic asthma by school age start with acute discrete episodes of pre-school wheeze before progressing to a multiple trigger pattern of symptoms. A proportion of children with viral wheeze progress to school age eosinophilic airway disease. The pathways to progression are very poorly understood ( 40 , 107 , 131 , 132 ). Important factors associated with progression include multiple early atopic sensitization and severe attacks of wheeze ( 133 ). We know that those with no personal or family atopic history are unlikely to progress, but although predictive indices ( 134 – 136 ) have a good negative predictive value, unfortunately the positive predictive value not much better than 50%. Currently we know that in the pre-school years those who develop school age asthma lose lung function, which is never regained throughout life ( 137 , 138 ); and they develop airway remodeling and eosinophilic inflammation. Although there is active research in the field ( 139 ) we do not have good predictive biomarkers nor do we understand the endotypes of progression or regression of the disease, nor do we have any therapeutic interventions. We know that ICS used early are not disease-modifying ( 140 – 142 ), but we do not know what might be useful. There are tantalizing hints that risk reduction is possible, from a randomized controlled trial of fish-oil supplementation ( 143 ) and the differences in atopic risk between the Amish and Hutterite communities, related to environmental exposures ( 144 ). This is another aspect of pathophysiology that requires more work.

Risk of Side-Effects

Clearly ICS doses should be the minimum required to control Type 2 inflammation. There is some evidence that the risk of side-effects relates more to an excessive dose of ICS relative to the degree of airway inflammation rather than the absolute dose prescribed. In a group of adult asthmatics, there was no difference in the pharmacokinetics of an intravenous dose of fluticasone, with similar area under the curves ( 145 ). However, when the same dose was given by inhalation, there was far greater absorption into the systemic circulations in the non-asthmatics. There was unfortunately no objective measurement of inflammation, but it is not unreasonable to suppose that overdosing relative to inflammation leads to side-effects.

Conclusion: Airway Phenotyping

Clearly we can learn a lot about the pathophysiology of the asthmas, and use this knowledge to improve diagnosis and treatment. We are still not achieving this in routine clinical practice, and this is shameful. However, even if we were phenotyping all patients and understanding pathophysiology with currently available tools, we need to progress to the next step, namely endotyping. The current position is described in the next section of this article.

Our Target: Endotyping the Airway

The general approach to airway endotyping has been to collect and characterize as far as possible large groups of patients, for example the U-BIOPRED ( 146 , 147 ) and SARP ( 148 ) cohorts, and use sophisticated—omics technologies to perform cluster analyses to try to determine the endotypes driving disease. However, caution is needed; whether a child is in a particular cluster will be driven by the underlying endotype, but also the effects of adverse environmental, infective or other factors which may vary over time, the contrasting effects of prescribed treatment, and whether the treatment is actually used by the patient. Environmental factors are unstable over time, and changes may be dramatic ( 108 , 109 , 149 , 150 ). Treatment adherence is highly variable, difficult to measure and will affect the airway. Hence an eosinophilic airway may be the final common pathway of combinations of a steroid resistant endotype; poor adherence to ICS treatment; and increased environmental allergen exposure. Clearly the management of these three factors is very different. Very few groups have studied longitudinal stability of phenotypes or endotypes, and a second, validation cohort is rarely used; when done, the evidence for stability is weak ( 151 ). Thus, our challenge is to differentiate what truly reflects a real endotype and what represents non-disease attributes (above). This is rarely addressed or even often identified as a problem.

Furthermore, most of these analyses are in patients with severe asthma, because mild asthma hardly merits study. However, most patients referred with “severe” asthma would have mild asthma if they took their treatment ( 152 – 154 ). In this regard, in a recent GWAS there was substantial overlap between mild and moderate to severe asthma ( 155 ). Although the authors speculated that this related to epigenetic silencing of genes, and was therefore not reflective of gene expression, an alternative explanation is that many diagnosed as moderate to severe asthma in fact were non-adherent to treatment.

Endoyping Asthma With Omics Technology

The U-BIOPRED ( 146 , 147 ) and SARP ( 148 ) investigators, who have largely focused on severe asthma, albeit with additional controls, are the major groups exploiting -omics technology. Systems biology is increasingly used to allow clusters and phenotypes to emerge from the data ( 103 , 156 ) using an unbiased analysis, not confounded by pre-set ideas. This is impossible; there is inevitable investigator bias in selecting the data to collect and analyse. For example, until relatively recently, bacterial infection was not thought relevant to asthma, but this has been challenged (above); prior to this work, bacterial samples would not have been collected and analyzed.

Cluster Analyses: What Do They Tell Us?

The SARP investigators ( 157 ) identified four clusters: mild to moderate early onset asthma, normal body mass index and no or eosinophilic airway inflammation; the second had the same inflammatory characteristics, but the patients older, more likely to be obese, with impaired airway obstruction on spirometry and African Americans were over-represented. The last two exhibited had predominantly neutrophilic sputum; sputum eosinophilia was also sometimes seen. One of these clusters also contained older patients who were more likely to be obese and have severe asthma, obstructive spirometry and to be treated with oral corticosteroids. The final cluster was the oldest, with males over-represented, and more likely to be obese and prescribed complex medication regimes. As well as a lack of replication and assessment of cluster stability over time, the investigators could not dissociate the effects of disease from those of treatment. Furthermore, association does not prove causation, which could not be determined. Critically, this sort of cluster analysis did not appear to help us make progress in understanding or treating disease. This last point is underscored by another SARP analysis revealing this time five clusters ( 120 ) with no differences in outcomes, again questioning the usefulness of this approach.

The U-BIOPRED investigators identified four clusters in adults using sputum cell transcriptomics ( 158 , 159 ). They used clinical clustering and training and validation cohorts to define phenotypes ( 159 ) which were then used to assess differences in sputum proteomics and transcriptomics data. The first were well-controlled patients with moderate-to-severe asthma. The second was in smokers with late onset severe asthma, further characterized by chronic airflow obstruction. The only difference between this and the third cluster was that the latter contained non-smokers. The fourth cluster contained obese women who had uncontrolled severe asthma, normal lung function but multiple asthma attacks. There were differences in gene expression in these clusters, which adds validity to their findings.

Assessment of the temporal stability of clusters was performed by the ADEPT group ( 160 ). They performed a baseline cluster analysis in adults which were then re-assessed over time and also validated in a U-BIOPRED subset ( 161 ). They used sophisticated mathematical techniques which included fuzzy-partition-around-medoid clustering. They included including clinical and biomarker profiles. They also classified the patients into TH2 hi and TH2 lo using gene expression profiles on bronchial biopsies. They identified four phenotypic clusters. The first was characterized by mild, early onset disease, good spirometry, and little in the way of inflammation; that present was predominantly Type 2. The second contained moderately well controlled asthmatics who had mild airflow limitation and moderate airway responsiveness; they also had Type 2 inflammation. The third group were only moderately well controlled, had minor Type 2 inflammation or a non-eosinophilic, neutrophilic phenotype airway phenotype with predominantly fixed airflow obstruction. The fourth cohort had severe asthma with uncontrolled reversible airflow obstruction, a mixed and type 2 inflammatory picture. However, there was huge overlap between the clusters for almost every marker; this does not invalidate the study, but suggests that cluster analysis may be excellent for determining groups linked by common mechanisms, but has yet to been shown in any cluster analysis. Hence the role of cluster analyses is yet to be defined. There are commonalities and differences between studies, and they have not delivered endotypes.

Asthma Diagnosis Using Omics Technology

It is well known that asthma is poorly diagnosed ( 162 – 164 ), often objective diagnostic tests are not used, and those that are available are so crude when compared with the gene signature approaches used, for example, in tuberculosis diagnostics ( 165 , 166 ). Blood transcriptomics would be the ideal. Red cedarwood triggered asthma in adults has a gold standard diagnostic test, unlike most of the asthmas outside the workplace, namely bronchial challenge. In a small study split into two cohorts, discovery and validation, adults with red cedarwood asthma could be reliably diagnosed using a gene signature in peripheral blood ( 167 ). Confirmation in other settings is needed, but a gene signature approach would be a major step change on current diagnostic approaches.

The U-BIOPRED group ( 168 ) also used a training and validation set. They identified 1693 genes differentially expressed in adult asthmatics as against controls, with a bigger effect size in severe asthmatics. Unfortunately, and reducing the value of this approach, around 90% of the differences could be related solely to differences in peripheral blood white cell count. Pathway analysis showed that genes related to chemotaxis, migration and myeloid cell trafficking, and decreased development of B-cells, haematopoietic progenitor cells and lymphoid organs were involved in the differences, in both training and validation cohorts. The results were similar but less pronounced in mild-moderate asthmatics. Gene signatures of corticosteroid responsiveness also differed. However, the transcriptomics did not map to any clinical cluster ( 169 ). Again this calls into question the utility of this approach, certainly as a clinical tool, and highlights our lack of understanding of the complexity of asthma. It is possible that the results might have been different if airway cells had been used, as being closer to the pathological process.

Asthma Pathophysiology: Hypothesis Generating Studies

Gene expression is regulated in part by non-coding RNA, and this has been a subject of asthma research. In adults with severe asthma, activation status of CD4 and CD8 lymphocytes was related to non-coding RNA expression. There were significant changes in CD8 but not CD4 cells, Multiple pathways involved in T-cell activation were enhanced and there were many changes in miRNA expression ( 170 ). This is observational study, and very preliminary, but an important starting point. The rapidly expanding field of the role of micro-RNAs has been reviewed in detail elsewhere ( 171 ).

Asthma Pathophysiology: Exploring Endotypes of Inflammation

Although the ideal is one endotype susceptible to a single biological, the reality is likely to be much more complex. Cytokines and chemokines were measured in sputum from subjects in the SARP group with varying severities of asthma, and unbiased factor analysis was used to try to define specific inflammatory pathways ( 172 ). There were complex inflammatory protein interactions identified by factor analysis. Severe asthma patients had nine increased and four decreased proteins compared to mild asthma subjects. Twenty-six mediators were significantly associated with an increasing single induced sputum leucocyte type: sixteen with neutrophils; 5 with lymphocytes; IL-15 and CCL15/MIP1δ with macrophages; interestingly, only IL-5 with eosinophils; and IL-4 and TNFSF10/TRAIL with airway epithelial cells. Forty three cytokines, chemokines, and growth factors which had no missing data were mapped onto the first 10 factors, containing mixes of Th1, Th2, Th9, and Th17 inflammatory and anti-inflammatory proteins, rather than pure pathways. Hence focus on a single specific mediator or pathway is likely an oversimplification of the complex reality of the asthmatic airway.

In a further study, the U-BIOPRED investigators started by defining phenotypes from sputum cytology, either eosinophil- and neutrophil-predominant. Next, they used sputum plugs to generate Affymetrix arrays and analyzed the data were analyzed using hierarchical, unsupervised clustering. They identified three transcript associated clusters (TACs). The first was contained oral corticosteroid dependent patients who had frequent asthma attacks, severe airflow obstruction, and the highest sputum eosinophil counts and FeNO levels. Immunologically, the receptors Il33R, CCR3 and TSLPR were upregulated and there was the strongest IL-13/TH2 and ILC2 gene signatures. The second cluster was clinically characterized by sputum neutrophilia, a raised serum CRP and eczema, and immunologically by IFN-, TNF-α- and inflammasome related genes being upregulated. The final cluster had moderate sputum eosinophilia and better spirometry, but despite sputum eosinophilia was immunologically characterized by upregulation of genes of metabolic pathways, ubiquitination and mitochondrial, with surprisingly, no TH2 signature. This important paper again highlights that eosinophilia is not synonymous with TH2 activation, confirming our own findings in severe asthma ( 26 ).

A pioneering study used transcriptomics of bronchial brushings and biopsies to determine TH2 hi and TH2 lo subgroups of mild to moderate asthmatics based on TH2 gene signatures ( 173 ). The TH2 hi subgroup had elevated peripheral blood levels of periostin (which is also derived from growing bone, so cannot be used in pediatrics), CLCA1 and Serpin B2, and eosinophilic airway inflammation which was ICS responsive. A subsequent study ( 174 ) using airway epithelial cell gene expression in adults confirmed this finding, but found that non-invasive biomarkers such as periostin were not sufficiently sensitive. The U-BIOPRED subsequently identified two steroid-resistant, eosinophilic subgroups in severe asthmatics ( 175 ); one with high mucosal eosinophilia, raised FeNO, asthma attacks and oral corticosteroid use; by contrast, the second eosinophilic group was more obese. We previously noted that sputum and BAL eosinophils correlate with each other, but not with mucosal biopsy eosinophils ( 15 ), but which is most important under what circumstances has not been determined. The U-BIOPRED investigators also described two non-eosinophilic groups, and developed model to predict the likelihood of the patient being steroid responsive. It is very clear that there are non-inflammatory phenotypes of severe asthma, and also that mucosal and BAL eosinophilia is not synonymous with Type 2 inflammation ( 176 ).

A further U-BIOPRED study highlighted the IL6 pathway as a potential cause of eosinophilic inflammation independent of TH2 cytokines ( 177 ). Activation of IL-6 trans signaling in air-liquid interface cultures of bronchial epithelial cells reduced the integrity of the epithelium. Associated with this was a specific signature enriched in airway remodeling genes. This signature identified a subgroup of adult asthmatics with increased epithelial expression of these inducible genes in the absence of systemic inflammation. There was an overrepresentation of patients with frequent attacks, peripheral blood eosinophilia, and submucosal of T cells and macrophage infiltration. TLR receptor pathway genes were upregulated, but cell junction genes expression was reduced. Sputum sIL6R and IL6 levels correlated with sputum markers of innate immune activation and airway remodeling. This study further evidence that there is a subset of asthmatic patients with no evidence of Type 2 inflammation; it may be that IL6 is driving airway inflammation and epithelial dysfunction in this group of patients.

The IL1 pathway may also be important ( 178 ). Sputum transcriptomics were compared in severe and mild-moderate adult asthmatics with eosinophilic and neutrophilic asthma. The investigators reported that IL1RL1 gene expression was associated with severe eosinophilic asthma, whereas NLRP3 inflammasome expression was highest in those with severe, neutrophilic asthma. These changes were only seen in induced sputum, not in bronchial brushings or biopsy specimens, underscoring the need to study multiple tissues if pathophysiology is to be understood.

Finally, FeNO is a well-known as an asthma biomarker, but whether more than one pathway results in increases has been little studied. The SARP team used a microarray platform to relate FeNO to bronchial airway epithelial cell gene expression ( 179 ). They identified 549 genes whose expression correlated with FeNO. They used k-means to cluster the patient samples and found that a total of 1,384 genes were identified in nine gene groups. Although type 2 inflammation genes were present, novel pathways, including those related to neuronal function, WNT pathways, and actin cytoskeleton, were also discovered, suggesting novel and as yet poorly characterized inflammatory pathways were at play in asthma.

Taken together, these studies suggest that in particular in severe asthma, there are multiple endotypes, possibly co-existing in some patients. There is far more to asthma pathophysiology than Type 2 inflammation. We have much more to learn from harnessing omics technology to the study of the asthmas.

Asthma Pathophysiology: Persistent Airflow Limitation

As discussed above, there are multiple contributory factors to persistent airflow limitation, including congenital and acquired remodeling, so it is likely that multiple genes are involved. The UBIOPRED group ( 180 ) used Gene Set Variation Analysis (GSVA), as a means of detecting underlying endotypes in such heterogeneous samples. Severe adult asthma patients from the U-BIOPRED cohort with persistent airflow limitation defined as post-bronchodilator FEV 1 /FVC below the lower limit of normal) were compared with asthmatics with normal spirometry. Gene expression was assessed on the total RNA of sputum cells, nasal brushings, and endobronchial brushings and biopsies. Fourteen differentially enriched gene signatures were identified that were associated with ICS, eosinophils, IL13, IFN-α, specific CD4 + T-cells and airway remodeling. There was a differentially expressed gene network associated with remodeling solely in the airway wall.

Asthma Attacks: Can We Do Better?

Chitinase-like protein YKL-40 modulates airway inflammation and serum levels are associated with asthma severity ( 181 ). In another SARP study ( 182 ), adult asthmatics were analyzed to determine if there were clusters based on YKL-40 levels, and the findings were validated in SARP. Sputum transcriptome analysis were used to demonstrate molecular pathways associated with YKL-40 clusters, of which four could be identified. Those with high serum YKL-40 were associated with earlier onset and longer duration of disease, severe airflow obstruction, and near-fatal asthma attacks. The cluster with the highest serum YKL-40 levels had adult onset disease and less airflow obstruction, but frequent attacks. Interestingly, and despite the fact that attack frequency was an important correlate of these clusters, an airway transcriptome analysis showed activation of non-type 2 inflammatory pathways. This study provides further evidence for the importance of non-TH2 pathways, and, although this needs validation, possibly suggests that serum YKL-40 levels may help risk-stratify patients.

Future Risks: Progression From Pre-school Episodic Wheeze to School Age Eosinophilic Airway Disease

This is an extremely complicated subject which is largely beyond the scope of this review. We know that antenatal and postnatal tobacco and pollution exposure are important factors impacting future lung health, but we know little or nothing of the molecular pathways to disease [see review Bush ( 121 )]. Furthermore, although we can predict who are low risk children, we are poor at predicting high risk, what the pathways to eosinophilic asthma actually are, and how we can reduce risk, either on a population or individual level. We have some largely descriptive –omics data which hint at pathways, but our knowledge gaps are huge.

Gene expression profiles were studied in transient and persistent wheezers using peripheral CD4+ve cells, and compared to normal, non-wheezing controls ( 183 ). The study was observational and descriptive, but did describe differences in gene expression between the two wheezing groups, with some commonalities in the paths involving proliferation and apoptosis of T-cells. Another group prospectively followed 202 preschool wheezers to school age, and testing the hypothesis that the use of volatile organic compounds (VOCs) and exhaled breath condensate would enhance the prognostic value of conventional predictive indices ( 184 ). They showed that VOCs and possibly inflammation related genes (TLR-4, catalase, TNF-α) improved predictive of persistent wheeze, but this study is also realm, and hypothesis generating, requiring validation in another cohort.

How Will We Make OMICS Work in Practice?

When clinically indicated, invasive techniques can be used to discover novel mechanisms and pathways, but these will be only applicable in really severe cases, not in more mildly affected infants and children. For most cases, non-invasive approaches must be found, especially in children. Blood, urine and induced sputum can and should be routine clinical tests, there are other accessible biosamples which should be evaluated. Exhaled breath analysis is non-invasive, requires only passive co-operation, and with modern analytical techniques can give point of care answers. Investigators can distinguish different airway diseases in adults (COPD, asthma) from a breathprint of VOCs ( 185 , 186 ). In children, 8 of 945 compounds studied could differentiate asthmatics from controls with a sensitivity of 89% and a specificity of 95% ( 187 ). There has been considerable interest in sophisticated mass spectrometry techniques, which can be applied for example to skin secretions, in order to detect airway infection in CF ( 188 ). The true test of the utility of these techniques will be whether they can differentiate children with non-specific respiratory symptoms from true asthmatics, and predict steroid responsiveness in the asthmatics. Perhaps in the future we will have a pediatric “Breathalyzer” which will give a readout of the important biomarkers to tell us the diagnosis, what endotypes are at play, and how best to treat the child.

Summary and Conclusions

There is no doubt we have incredible opportunities within reach to transform the diagnosis and treatment of the asthmas. We have powerful tools and –omics technologies available to us, as well as pathway specific monoclonals. These need to be targeted rationally. We need to reflect that the specific designer molecules which are transforming CF ( 2 – 4 ) would have been discarded as ineffective if they had been applied indiscriminately to all CF patients, and not to gene class specific sub-endotypes. The CF community are progressing to ex vivo testing of novel compounds ( 189 , 190 ) and we must do the same for the asthmas, to produce truly personalized airway medicine.

There are questions specifically pertaining to the asthmas that we need to address. We need to understand steroid resistant, particularly non-TH2 driven eosinophilia, and apparently non-inflammatory asthma pathways. We have argued elsewhere that children with refractory difficult asthma (for example, those persistently not taking basic medications) should not be denied biologicals to prevent them from dying ( 191 ); even in this group, identification of the endotype will be needed to ensure the right child gets the right biological. But we also need to appreciate the diversity of the asthmas—Type 2 inflammation, although obviously important, is only one part of the picture, and we need to better are specific appreciate the whole.

But finally we must appreciate that the more sophisticated and expensive approaches to monitoring and treatment are available, the more clinical skills become relevant ( 192 ). We will need better get the basics right, rather than immediately deploy the latest gene probe test and expensive therapeutic molecule. At bottom, most pediatric asthma is a simple disease to diagnose and treat if basic measurements are made and the child is given low dose therapy appropriately and regularly. We should never lose sight of this reality, and never stop using our clinical skills, and honing those skills, to get the basics right, working in a multidisciplinary team alongside the child and family.

Author Contributions

The author confirms being the sole contributor of this work and has approved it for publication.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

1. ^ https://ginasthma.org/

2. ^ https://www.rcplondon.ac.uk/projects/national-review-asthma-deaths/

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Keywords: biomarker, transcriptomics, bronchial biopsy, bronchial brushings, induced sputum, airway inflammation, asthma phenotype, endotype

Citation: Bush A (2019) Pathophysiological Mechanisms of Asthma. Front. Pediatr. 7:68. doi: 10.3389/fped.2019.00068

Received: 04 January 2019; Accepted: 19 February 2019; Published: 19 March 2019.

Reviewed by:

Copyright © 2019 Bush. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Andrew Bush, [email protected] ; orcid.org/0000-0001-6756-9822

This article is part of the Research Topic

Difficult and Severe Asthma in Children

Asthma: pathophysiology, causes and diagnosis

Despite asthma affecting more than 5.4 million people in the UK, there is no gold standard test and diagnosis is based on signs and symptoms.

Centre Jean Perrin / Science Photo Library

There is no single cause for asthma, and a range of environmental and genetic factors are known to influence its development. These include premature birth and low birth weight and exposure to tobacco smoke (especially if the mother smokes in pregnancy). It is more common in prepubertal boys, but girls are more likely to remain asthmatic in adolescence.

A diagnosis of asthma in both children and adults is based on assessment of symptoms. The classic signs of asthma are wheezing (especially expiratory wheezing), breathlessness, coughing (typically in the early morning or at night time) and chest tightness. Children and adults with a high probability   of asthma on assessment usually start a treatment trial with a corticosteroid such as beclometasone. Children and adults with an intermediate probability of asthma are assessed with lung function tests such as spirometry, peak flow and airway responsiveness to confirm the diagnosis.

Asthma is a chronic inflammatory disorder of the airways. Chronic inflammation causes an increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible, either spontaneously or with treatment [1] .

It is estimated that more than 5.4 million people in the UK are currently diagnosed with asthma, of whom 1.1 million are children. In the UK, asthma causes 1,200 deaths each year, or one death from asthma every eight hours. This number has remained stable over the past few years despite raised awareness [2] , [3] .

Pathophysiology

Asthma is usually mediated by immunoglobulin E (IgE) and precipitated by an allergic response to an allergen. IgE is formed in response to exposure to allergens such as pollen or animal dander [4] . Sensitisation occurs at first exposure, which produces allergen-specific IgE antibodies that attach to the surface of mast cells. Upon subsequent exposure, the allergen binds to the allergen-specific IgE antibodies present on the surface of mast cells, causing the release of inflammatory mediators such as leukotrienes, histamine and prostaglandins. These inflammatory mediators cause bronchospasm, triggering an asthma attack.

If an attack is left untreated, eosinophils, T-helper cells and mast cells migrate into the airways [1] . Excess mucus production caused by goblet cells plug the airway and, together with increased airway tone and airway hyperresponsiveness, this causes the airway to narrow and further exacerbates symptoms.

There is some evidence to suggest that airway remodelling can occur if asthma is poorly controlled over a period of years. Chronic inflammation causes bronchial smooth muscle hypertrophy, the formation of new vessels and interstitial collagen deposition, which results in persistent airflow obstruction similar to that seen in patients with chronic obstructive pulmonary disease (COPD) [5] .

Although there is no single cause of asthma, certain environmental and genetic factors are known to contribute to the development of the condition. These include:

• Family history of asthma (especially a parent or sibling) or other atopic conditions (for example, eczema or hayfever)
• Bronchiolitis in childhood — 40% of children exposed to respiratory syncytial virus or parainfluenza virus will continue to wheeze or have asthma into later childhood [1]
• Exposure to tobacco smoke, particularly if the mother smokes during pregnancy
• Premature birth
• Low birth weight
• Occupational exposure to plastics, agricultural substances and volatile chemicals, such as solvents. Asthma is more prevalent in industrialised countries
• A body mass index of 30kg/m 2 or more
• Bottle feeding — evidence shows that if an infant is breastfed there is a decreased risk of wheezing illness compared with infants who are fed formula or soya-based milk feeds [3]

Environmental and cultural factors in recent decades, such as changes in housing, air pollution levels and a more hygienic lifestyle (reducing early exposure to allergens), may also increase the risk of asthma.

Asthma is more common in prepubertal boys, but boys are more likely to grow out of their asthma during adolescence than girls [1] .

Phenotyping is becoming increasingly important for clinicians in determining why some people are predisposed to develop asthma and others are not. Furthermore, it is believed that a person’s phenotype may also contribute to the way he or she responds to treatment [6] . For example, variations in the gene that codes for beta-adrenoceptors have been linked to differences in how cells respond to beta-agonists. In the future, as more information emerges, it may be possible to tailor treatments for individual patients to enhance response — which is particularly important as more high-cost, highly specific medicines are being developed [3] , [6] .

Clinical features

There are many factors likely to trigger an asthma attack, and potential causes will vary between patients. Possible triggers include: the common cold; allergens (e.g. house dust mites, pollen); exercise; exposure to hot or cold air; medicines (e.g. NSAIDs); and emotions such as anger, anxiety or sadness.

The classic signs of asthma are wheezing (especially expiratory wheezing), breathlessness, coughing (typically in the early morning or at night time) and chest tightness. Wheezing that occurs as a result of airway bronchoconstriction and coughing are likely to be caused by stimulation of sensory nerves in the airways.

In a severe exacerbation, when there is severe obstruction of the airway, wheeze may be absent and the chest may be silent on auscultation (listening to the chest). In such cases, other signs such as cyanosis and drowsiness may be present, and the patient may be unable to complete full sentences. Severe exacerbations of asthma are medical emergencies.

Diagnosis of asthma is based on medical history, physical examination, lung function testing and response to medication (see ‘Diagnosis of asthma’). There is no gold standard test that can be used to confirm the diagnosis.

Diagnosis of asthma [1]

Clinical features that increase the probability of asthma

• More than one of the following symptoms: wheeze, cough, difficulty breathing, chest tightness, particularly if these are frequent and recurrent; are worse at night and in the early morning; occur in response to, or are worse after, exercise or other triggers; occur apart from colds; are associated with taking aspirin or beta-blockers in adults
• Personal history of atopic disorder
• Family history of atopic disorder and/or asthma
• Widespread wheeze heard on auscultation
• History of improvement in symptoms or lung function in response to adequate therapy (in children)
• Otherwise unexplained peripheral blood eosinophilia, or low forced expiratory volume in one second or peak expiratory flow (in adults)

Clinical features that lower the probability of asthma

• Symptoms with colds only
• Isolated cough with no wheeze or difficulty breathing, or history of moist cough (in children)
• Chronic productive cough with no wheeze or difficulty breathing (in adults)
• Prominent dizziness, light-headedness, peripheral tingling
• Repeatedly normal physical examination of chest when symptomatic
• Normal peak expiratory flow or spirometry when symptomatic
• Cardiac disease (in adults)
• Voice disturbance (in adults)
• History of smoking for more than 20 pack-years (in adults)

Children and adults with a high probability of asthma on assessment usually start a treatment trial, where their response is assessed using spirometry. Children and adults with an intermediate probability of asthma usually have lung function tests conducted, such as spirometry, peak flow and airway responsiveness.

Spirometry can be used to measure lung function and is a good guide to diagnosing asthma in adults. It is not always definitive; normal findings do not exclude a diagnosis of asthma if the patient is well at the time of testing. The spirometric measures used in the diagnosis of asthma are:

• Forced vital capacity (FVC) — the total volume of air expelled by a forced exhalation after a maximal inhalation
• Forced expiratory volume in one second (FEV 1 ) — the volume of air expelled in the first second of a forced exhalation after maximal inhalation
• FEV 1 /FVC ratio

An FEV 1 /FVC ratio below 0.7 is suggestive of airway obstruction, which can increase the probability of asthma, but it can also be caused by conditions such as COPD.

Peak expiratory flow  using a peak flow meter   measures the resistance of the airway. Although it is not as accurate as spirometry, it can be used to demonstrate variability of lung function throughout the day. Measurements should be taken in the morning and evening (as a minimum) and recorded in a diary to see if there is diurnal variability. Readings are dependent on technique and expiratory effort, therefore the best of three expiratory blows from total lung capacity should be recorded during each session. Peak flow diaries are better for monitoring patients with an established diagnosis of asthma rather than for making an initial diagnosis [1] , [3] .

Assessment of airway responsiveness using inhaled mannitol or methacholine is used for diagnosing patients with normal or near normal spirometry who have a baseline FEV 1 of less than 70% of that predicted using population data. Both drugs induce bronchospasm [1] , [3] . A fall in FEV 1 of more than 15% following a test with mannitol is a specific indicator for asthma. This assessment is useful for distinguishing asthma from other common conditions that can be confused with asthma (for example, rhinitis, gastro-oesophageal reflux, heart failure and vocal cord dysfunction).

A treatment trial in adults involves a patient being prescribed a six-to-eight week trial of inhaled beclometasone 200µg (or equivalent) twice a day, or two weeks of oral prednisolone 30mg daily. An improvement in FEV 1 of 400ml or more following the trial is strongly suggestive of an underlying diagnosis of asthma. Spirometric assessment after a treatment trial is more effective for patients with known airflow obstruction, and is less helpful for patients who had near normal lung function before the trial.

Non-invasive testing of sputum eosinophils and exhaled nitric oxide concentration can also help guide a diagnosis of asthma. A raised sputum eosinophil count (>2%) is seen in around 70–80% of patients with uncontrolled asthma. However, patients with COPD or chronic cough may also exhibit abnormal levels of eosinophils and the test should not be used for definite diagnosis [7] . Sputum eosinophils and exhaled nitric oxide concentration are not routinely measured in general practice, but are in designated difficult asthma clinics [3] . An exhaled nitric oxide level of more than 25 parts per billion supports a diagnosis of asthma.

Assessing asthma control

Many people with asthma do not have their condition well controlled. A survey of 8,000 people with asthma in Europe between July 2012 and October 2012 found that despite 91% of patients considering themselves as having well controlled asthma, only 20% of cases were controlled according to standards set out by national and international guidance [8] .

The aim of asthma management is to achieve and maintain complete control of the disease. This is defined as having:

• No daytime symptoms or night time awakening due to asthma
• No need for rescue medication
• No exacerbations
• No limitations on activity including exercise
• Normal lung function
• Minimal side effects from medication

It is important that control of asthma is measured objectively. One effective way to assess the level of control is the Asthma control test questionnaire (available from asthma.com ). This validated five-point questionnaire is a simple and easy way for patients to self assess their asthma control and guide healthcare professionals to develop a treatment plan in accordance with the results obtained [1] .

[1]  British Thoracic Society and Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Clinical Guideline 141. London: BTS. October 2014.   

[2]  Royal College of Physicians (London).  Why asthma still kills. London: RCP. May 2014.  

[3]  Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Geneva: GINA. 2014.   

[4]  Barnes P. Similarities and differences in inflammatory mechanisms of asthma and COPD. Breathe 2011;7:229–238.

[5]  Dournes G & Laurent F. Airway remodelling in asthma and COPD: findings, similarities and differences using quantitative CT. Pulmonary Medicine 2012.

[6]  Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches.  Nat Med 2012;18:716–725.

[7]  Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophilia counts: a randomised controlled trial. The Lancet 2002;360:1715–1721.

[8]  Price D, van der Molen T, Fletcher M. Exacerbations and symptoms remain common in patients with asthma control: a survey of 8000 patients in Europe. Abstract presented at the European Respiratory Society conference 2013.

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Pathophysiology Of Asthma

• Category Health
• Subcategory Disease
• Topic Asthma

Asthma is a spasmodic contraction of the smooth muscle in the walls of the smaller bronchi and bronchioles and an enduring condition, which causes occasional breathing difficulties of a person and one of the major reasons behind poor health among the children and the adults that affect their quality of life (Crowley, 2013). According to Foundation, (2018), 8 million people – over 12% of the population – have been diagnosed with asthma. This essay attempts to demonstrate the pathophysiology and key clinical presentations of asthma by considering the case study scenario of Carol, a 22 years old Caribbean lady, who was diagnosed with asthma when she was 5years old is currently prescribed an inhaled corticosteroid (equivalent to 800mcgs beclomethasone daily). She is admitted into theatres for laparoscopic operation. Later, the essay would also focus on the role of the ODP in providing relevant care during post-operative to the patient considering the present HCPC practices and NICE guidelines.

In asthma, airflow restriction is recurrent due to multiple changes within the airway of the affected individuals. It is believed to be a disease of chronic inflammation of the bronchial surface, and it is this chronic inflammation that appears to play a major role in the activity of the airway. Recognised triggers include physical exertion, allergens, medication, occupational infection, emotions and stress. As mentioned in the case study, shortness of breath is one of the most common clinical manifestations of asthma. Narrowing down of airway or bronchoconstriction is a major physiological event in asthma that affects the subsequent airflow. Contraction of the bronchial smooth muscles occurs rapidly that further narrows down the airways while exposing to various stimuli that include irritants or allergens. Mast cells of the immune system, found in loose connective tissue, when triggered by a substance or mechanism releases vasoactive chemical mediators, including, histamine, bradykinin, leukotrienes, cytokines, and prostaglandins. These mediators contract the airway smooth muscle directly (NHLBI, 2007). Neutrophils, lymphocytes, and eosinophils infiltrate the cells of the bronchial lining through chemotactic chemical mediators released from mast cells. These target the respiratory system and cause bronchoconstriction, vascular congestion, vasodilation, increases in capillary permeability, mucosal oedema, impaired mucociliary action, and increased mucus production, which leads to an increase in airway resistance. Plugging of mucus can also occur in the smaller bronchioles. These changes are difficult to manage with usual treatments. Inflammation plays a crucial role in the pathophysiology of asthma. The inflammation of the airways involves the interaction of multiple cell types and mediators and subsequently, gives rise to the characteristics of asthma: airway restriction and bronchial inflammation cause repeated incidents of wheeze, cough and thereby, shortness of breath (Kudo, et al., 2013). Han, et al., (2018) harangued that the outline of inflammation does not depend upon the sternness, duration and persistence of the disease nonetheless, the response of structural cells and cellular profile are rather stable. Thus, shows the evident that activation of mast cells provisions secretions of bronchoconstriction mediators like prostaglandin D2, cysteinyl-leukotrienes and histamine. Allergen activation takes place through high-affinity IgE receptors and sensitized mast cells are activated by the osmotic stimuli due to exercise-induced bronchospasm. Larsson, et al., (2011) stated that elevation in the number of mast cells is linked with airway hyper-responsiveness. In the presence of a smaller number of allergens, mast cells could release good number of cytokines in order to change the adjacent of the airways and increase inflammation. Cytokines modify and direct inflammatory responses in asthma and thereby, determine its intensity. Helper T cell 2 (Th2) derived cytokines, especially the IL-5 is necessary for the survival and differentiation of the eosinophils, IL-4 and IL-3are important for the cell differentiation and IgE formation respectively. Firm major cytokines like the tumour necrosis factor- ∝ and IL-1β intensify the inflammatory response that prolong the survival of the eosinophil within the airways (Lumb, 2017). These pathophysiological factors produce the typical clinical presentation of asthma, including wheezing and respiratory distress which the author will now discuss the signs and symptoms of asthma in the following paragraph.

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As mentioned earlier, this patient can suffer common symptoms include coughing, especially at night, wheezing, shortness of breath, and chest tightness, pain or pressure. Still, not everyone with asthma has the same symptoms in the same way. Symptoms are experienced when the airway tightens, inflame, or fill with mucus. Severe attacks are less common, but lasts longer and require medical help whereas, mild asthma attacks are generally more common. Recognising signs such as lose of breath, feeling tired, easily upset or moody, decrease or changes in lung function as measured on a peak flow meter can help avoid asthma attack on this patient. Treating carol with medicines such as aspirin or other nonsteroidal anti-flammatory drugs and nonselective beta-blockers might cause a trigger (NHLBI, 2014). This patient has a condition and has undergone surgery. Volatile and anaesthetic agents including drugs were administered, so managing asthma can be harder sometimes. Examples of conditions that can hinder the treatment and management includes a runny nose, sinus infection, reflux disease, psychological stress and sleep apnoea. Such conditions need treatment as part of an overall asthma care plan.

It is important to have asthma symptoms under control to decrease the risk of bad reactions because surgery can be very challenging for the human body. Pain is usually inevitable in asthmatic patients after surgery and may cause many days of grief. It is advisable to discontinue pain medication such as Ibuprofen as soon as possible after a procedure (Levy & G, 2001). This patient can get an asthma attack anytime since the whole process is nerve-racking, hence the need to monitor symptoms closely all the time. Under 2% of cases of bronchospasm occurs during general anaesthesia and most likely during induction. Asthma is not thought to increase the risk of post–operative pulmonary complications significantly. However, for some procedures poorly controlled asthma associated with significant coughing can lead to increased postoperative risks such as the increased risk of wound re-opening. Thorough evaluation before surgery is vital to perform a history, physical exam, and review recent medical use. If found that asthma is not optimally controlled it may require that any elective, non-emergent surgery be postponed. If still not sure a peak expiratory flow rate test is performed. 80% is predicted good, one-time peak flow test is not considered optimal. For higher-risk procedures of upper abdominal, thoracic or cardiac surgery, FEV1 (spirometry) is used for monitoring. An FEV1 of greater than 80% of predicted generally indicates good asthma control. Carol can opt-in for regional anaesthesia instead of general. The main benefit of regional is that it avoids the potential risk for airway complications when the airway is manipulated. Intensive treatment before surgery with a short dose of steroids and other treatment is prescribed for not optimally controlled asthma. In the event this patient is already on chronic oral steroids and having needed oral steroids in the last six months, IV steroids should be administered during procedure (Bass, 2015).

ODP play a crucial role in managing symptoms of this patient in order to alleviate the disease complication. Occurrence of depression with asthma in women like this patient is very common, and can influence behavioural factors, such as treatment compliance, self-assessment, and management of environment triggers, that can collectively result in poor asthma management and control (Frieri, et al., 2015). To achieve that the ODP should understand the pathophysiology of the illness and have an insight of patients’ developmental stage, age and other related factors that would help them to offer individualized care or patient-centred care. This requires tremendous social and psychological support and ODP play a crucial role in this regard by ensuring patients’ privacy while providing healthcare and respect their ethnical identity (Health, 2017). A study by Lin, et al., (2016) showed that patients with asthma had higher risk of post-operative pneumonia, spticemia, and urinary tract infection when compared with non asthmatic patients. Post operative adverse events are significantly increased among surgical patients with asthma who have pre-operative emergency visits, hospitalisation, or ICU stay. Appropiate skilled personnel should be provided to ensure that the patient is suitably recovered and sufficiently stable to be safely cared for after discharge. The NCEOPD, (2011) report found that patients whose condition was deteriorating were not always identified and refered to a higher level of care. Carol is at risk of clinical deterioration, and is vital that it is minimised through knowledge and understanding of the key areas of risks and local policies (NICE, 2012). The ODP can track and trigger early sign warnings by checking the patient’s pulse and respiratory rate, systolic blood pressure, temperature, and level of consciousness. Additional monitoring may include pain assessment, capillary refill time, percentage of oxygen administered, oxygen saturation, central venous pressure, infusion rates, and hourly urine output. Because this patient has undergone surgery, observing sighs of haemorrhage, shock, sepsis and the effects of analgesia and anaesthetic. It is therefore imperative to manage this patient’s pain, to ensure that the patient has adequate analgeia but is alert enough to communicate and cooperate with clinical staff during their postoperative stay (Wilson, 2006). Recording of signs and assesments is vital inline with guidance for record keeping (NHS, 2017). In case this patient suffers an asthma attack, supplementary oxygen, repeated inhaled bronchodilater and systematic corticosteroids is the mainway of treatment during the acute attack. Further treatment requirements and hospital admission is determined by the response to treatment. Patient with features of potentially life threatening who are not responding to treatment, or those with features suggesting that they are imminent risk of death, should be admitted to ICU or HDU. Ward admission is recommended if this patient’s repeated bronchodilater treaetment does not increase the FEV1 to >50-60% predicted, or if clinical features of severe asthma persists. Hospitalization positively and negatively affect both the adult and family. Positive side of hospitalization is that it promotes patient care and make people understand why seeking medical advice is important. Alternatively, hospital admission could increase stress on individuals, inadequate support of which could affect the quality of life of the patient and their family members A doctor or ODP should remain with this patient after initial treatment has started, or until clear improvement is noted. When an improvement is achieved, the emphasis shifts to investigation of the causes and circumstances of the severe attack, and arrangements are made for management. Following discharge, longterm treatment, the instituition of a self-management plan and appropiate follow-up arrangements are made (Hodder, et al., 2010).

It is crucial that doctors address the problems that may have led to an asthma attack before discharging the patient. This is because this patient is considered high risk patients who have poor self-management and often have inadaquate medical follow-up in the community. Prescription of regular inhaler corticosteroids and that their inhaler technique is intact should be checked prior to discharge. Arrangements should be made for medical follow up both with the GP and with the respiratory specialist in the case of life-threatening asthma (WebMD, 2018).

Communication theory, theories of integrated care and cognitive theory are considered good for this patient. Persuasion-Communication Model is deemed good for this patient because it presents a stepwise model of persuasion: exposure to a message, attention to that message, comprehension of the arguments and conclusion, acceptance of the arguments, retention of the content and attitude change. Both the patient and the healthcare staff are important factors in the source of the message and the recipient. Communication is vital as mentioned in the theory because it allows the patient to have a voice regarding their treatment (Cummings, et al., 2017). Theories of integrated care stress the radical or gradual redesign of the steps in providing care. For this patient, it includes collaborations of care providers, allocating tasks differently, transferring information more effectively, scheduling appointments and contacts more efficiently, and using new types of health professionals. Cognitive theory helps the ODP and other medical personnel to make rational decision if in order to provide optimal care, professionals must consider and balance the advantages of different alternative behaviours of the patient. Such theories regard the provision of convincing information about risks and benefits and pros and cons as crucial to performance change. This shows that the patient could take their own life decisions and thereby, they need to be involved in their care plan (Grol, et al., 2007). This plan, however, can be deterred when the patient is stressed due to pain or the stress of depending on other people. This could be sometimes life-threatening as they are still recovering from the operation. A prominent example in this context would be pressure to smoke, alcohol consumption and substance misuse that affect the health of the adults to a greater extent. It is evident that adults who are affected by asthma at a rate of 30-35% are cigarette smokers worldwide (AAAAI, 2018). Hence, it could be mentioned that Carol should be educated by a care professional, who could teach her about how asthma is affecting her health and encourage her for smoking cessation.

Person -centred care is also important while caring for this patient. This is because it makes the patient feel free from threat, both physically and psychologically. This type of approach is effective as it includes partnership building among the care professionals. This can only be achieved when there is a deep understanding, genuine, and acceptance in the relationship. This technique relies only on the personal qualities of the ODP/patient to build a non-judgemental and empathetic relationship (BAPCA, 2018).

There is no known asthma diet, because there are no foods that has been identified for reduce of airway inflammation. However, a good diet is important part of overall asthma treatment plan. Obesity is associated with severe asthma, so a regular exercising regime and healthy diet is encouraged. The nutritionist could develop proper diet chart for the asthma affected patient that would boost their immunity power and save them from rapid weight loss by rejuvenating body cells (WebMD, 2018). While individuals are living with an enduring disease, it is the healthcare professionals’ responsibility to teach them with coping mechanisms so that they have survive well for the rest of their lives without compromising the quality of their life.

In conclusion, it could be mentioned that Asthma is a chronic respiratory illness that affect the health and wellbeing of affected individuals, which currently has no cure. Research into this area is important. But likewise, it is important to try and see if there are ways to prevent children and adults getting asthma in the first place. The health care professionals should be supportive and help these patients to entree adequate care interrelated resources to meet their healthcare needs to a greater extent. The care professionals should provide culturally competent care and maintain equality in the healthcare system. The care professionals should make adult patients and their family members understand the importance of person-centred care that could help them to maintain their health and wellbeing throughout their lives. As, a patient that has undergone surgery phase, they should be provided with additional guidance and care so that they are not feel deprived and wound infection, while affected with a long-term illness. With the help of Cognitive and communication theory, this essay has strikingly illustrated the relevant aspects of care for asthma. In the meantime, research needs to concentrate on controlling asthma attacks which still kills people on a daily basis.

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Current Understanding of Asthma Pathogenesis and Biomarkers

Nazia habib.

1 Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA

Muhammad Asghar Pasha

2 Department of Allergy, Asthma, and Immunology, Albany Medical College, Albany, NY 12208, USA

Dale D. Tang

Asthma is a heterogeneous lung disease with variable phenotypes (clinical presentations) and distinctive endotypes (mechanisms). Over the last decade, considerable efforts have been made to dissect the cellular and molecular mechanisms of asthma. Aberrant T helper type 2 (Th2) inflammation is the most important pathological process for asthma, which is mediated by Th2 cytokines, such as interleukin (IL)-5, IL-4, and IL-13. Approximately 50% of mild-to-moderate asthma and a large portion of severe asthma is induced by Th2-dependent inflammation. Th2-low asthma can be mediated by non-Th2 cytokines, including IL-17 and tumor necrosis factor-α. There is emerging evidence to demonstrate that inflammation-independent processes also contribute to asthma pathogenesis. Protein kinases, adapter protein, microRNAs, ORMDL3, and gasdermin B are newly identified molecules that drive asthma progression, independent of inflammation. Eosinophils, IgE, fractional exhaled nitric oxide, and periostin are practical biomarkers for Th2-high asthma. Sputum neutrophils are easily used to diagnose Th2-low asthma. Despite progress, more studies are needed to delineate complex endotypes of asthma and to identify new and practical biomarkers for better diagnosis, classification, and treatment.

Asthma is a heterogeneous lung disease that affects more than 300 million people worldwide [ 1 ]. Asthma is characterized by variable airflow obstruction and airway hyperresponsiveness (AHR), leading to episodic and reversible bronchoconstriction, because of an exaggerated airway-narrowing response to many environmental triggers, such as allergens. Traditionally, the illness is classified into two groups: extrinsic and intrinsic asthma. Extrinsic asthma is also known as allergic asthma, which is caused by allergens and mainly attributed to aberrant T helper type 2 (Th2) inflammation. Intrinsic asthma is triggered by various factors, such as aspirin, pulmonary infection, exercise, cold, stress, obesity, etc.

Recently, based on the status of Th2 inflammation, the disease has been classified into two groups: Th2-high and Th2-low asthma. Th2-high asthma is characterized by eosinophilic airway inflammation, which is associated with increased blood eosinophil counts or elevations of fractional exhaled nitric oxide (FeNo), whereas Th2-low asthma includes neutrophilic asthma and paucigranulocytic asthma. The coexistence of eosinophilic and neutrophilic airway inflammation is considered mixed granulocytic asthma [ 1 , 2 ]. The pathological mechanisms of asthma are complex, varying in different phenotypes caused by different environmental triggers, ages, obesity, genetic factors, etc. In addition to airway inflammation, there is emerging evidence to suggest that inflammation-independent processes also contribute to asthma pathogenesis. Furthermore, biomarkers of a disease are traceable substances that are useful for diagnosis, classification, and treatment. This review is focused on the pathogenesis and biomarkers of asthma induced by allergens, infection, and pollutants.

1. Pathological Mechanisms of Asthma

Although asthma is classified into Th2-high and Th2-low asthma, the disease can be induced by mixed airway inflammation. Patients may have Th2-high asthma in the early stage and have Th2-low asthma in a later stage or vice versa; or Th2-high asthma and Th2-low asthma occur concurrently. Because of the complexity of asthma, we discuss the mechanisms of Th2-high asthma, Th2-low asthma, and other mechanisms separately.

1.1. Mechanisms of Th2-High Asthma

Th2 cells are a distinct lineage of CD4 + effector T cells that secrete interleukin (IL)-4, IL-5, IL-13, and IL-9. Approximately 50% of mild-to-moderate asthma and a large portion of severe asthma is induced by Th2-dependent inflammation [ 1 , 2 ]. Since Th2-high asthma has been reviewed in detail elsewhere [ 2 , 3 , 4 ], we summarize the key points for the mechanisms of Th-2 high asthma.

Th2 inflammation has two major phases: 1. Sensitization: When allergens enter the low airways, antigen-presenting cells process and present the allergens to Th2 cells, which secret Th2 cytokines, including IL-5, IL-4, and IL-13. IL-4 and IL-13 activate B cells, which produce IgE and bind to FcεRI of mast cells. 2. Challenge: When the same allergens enter the airways, they bind to IgE, which induces mast cells to release mediators, such as leukotrienes (LTs), histamine, and ILs. In addition, allergens act on cholinergic nerves to release acetylcholine. These mediators and neurotransmitters irritate airway smooth muscle and induce bronchoconstriction [ 1 , 2 , 3 ]. In addition, IL-5 facilitates eosinophil production, maturation, and recruitment to the lungs [ 5 ]. Eosinophils also release mediators, including major basic protein (MBP), which stimulates mast cells to release histamines and LTs. MBP also inhibits M 2 receptor and promotes acetylcholine release from cholinergic nerves and induces bronchospasm [ 6 ]. Furthermore, IL-13 directly sensitizes airway smooth muscle contraction, stimulates epithelial cells to secret mucins, and induces fibrosis [ 7 ] ( Figure 1 ).

Mechanism of Th2-high asthma. When allergens enter the low airways, dendritic cells (DCs) present the allergens to Th2 cells, which secrete Th2 cytokines, including interleukin (IL)-5, IL-4, and IL-13. IL-4 and IL-13 activate B cells, which produce IgE. IgE subsequently binds to surface of mast cells. When the same allergens enter the airways, they interact with IgE, which induces mast cells to release mediators, such as leukotrienes (LTs), histamine, and ILs. These mediators irritate airway smooth muscle and induce bronchoconstriction. In addition, IL-5 facilitates eosinophil recruitment to the lungs. Eosinophils also release mediators, including major basic protein (MBP), which stimulates mast cells to release histamines and LTs. MBP also inhibits M 2 receptor and promotes acetylcholine release from cholinergic nerves and induces bronchospasm. Furthermore, IL-13 directly sensitizes airway smooth muscle contraction, stimulates epithelial cells to secret mucins, and induces fibrosis. Th9 cells can secrete IL-9, which activates Th2 cells and promotes mast cell accumulation. Lastly, epithelium injury by infection and pollutants induces release of cytokines, including thymic stromal lymphopoietin (TSLP), IL-25, and IL-33, which activate type 2 innate lymphoid cells (ILC2) and produce Th2 cytokines, such as IL-5 and IL-13.

Recent studies demonstrated that the airway epithelium produces cytokines in response to injury, infection, and pollutants. These epithelial-derived cytokines include thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. TSLP, IL-25, and IL-33 activate type 2 innate lymphoid cells (ILC2), which generate Th2 cytokines, such as IL-5 and IL-13 and induce Th2 lung inflammation [ 1 , 2 ]. Additionally, there is evidence to suggest that IL-33 may directly affect mast cell activation, airway smooth muscle migration, and asthma phenotype [ 8 ] ( Figure 1 ).

Th9 cells and IL-9 are also involved in Th2 lung inflammation [ 9 ]. Th9 cells produce the cytokines IL-9, IL-10, and IL-21; however, IL-9 is likely to contribute to asthma pathology. Because of its pleiotropic effects, IL-9 influences a variety of distinct cell types, such as T cells, B cells, mast cells, and macrophages. IL-9 may promote Th2 inflammation by activating Th2 cells and by increasing mast cell accumulation [ 9 ]. IL-9 may also activate Arg1 + interstitial macrophages, which secrete the chemokine CCL5. CCL5 then recruits eosinophils, T cells, and monocytes into the lungs to propagate type 2 inflammation [ 10 ] ( Figure 1 ).

Natural killer T (NKT) cells are a distinct subset of lymphocytes that are abundant in the lungs as well as lymphoid organs. It was proposed that NKT cells secrete IL-4 and IL-13 or facilitate Th2 cells to increase production of IL-4 and IL-13 [ 11 ]. However, other studies do not support this notion [ 12 , 13 ].

Regulatory T cells (Tregs) are a specific CD4 + T cell population that act to suppress immune response, thereby maintaining homeostasis and self-tolerance. Tregs have been classified based on the expression of the transcription factor FOXP3. Tregs may inhibit asthma pathogenesis by suppressing the activation/functions of ILC2, mast cells, antigen-presenting cells, Th1/Th2/Th17 cells, eosinophils, neutrophils, and B cells [ 14 ].

One of the targets of Th2 cytokines is periostin, a matricellular protein that is a dynamically expressed non-structural protein present in the extracellular matrix. Periostin expression is upregulated by IL-4 and IL-13 in cultured bronchial epithelial cells and bronchial fibroblasts [ 15 ] and is one of the most differentially expressed bronchial epithelial genes between asthmatic patients and healthy control subjects [ 16 ]. The role of periostin in asthma is still under investigation. There are reports to suggest that periostin supports adhesion and migration of IL-5-stimulated human eosinophils and Th2 inflammation in asthma [ 17 ]. On the other hand, other studies suggest that periostin plays a protective role, rather than detrimental role in asthma. Periostin positively regulates TGF-β production, which promotes T-regulatory cell differentiation. Differentiated T cells inhibit airway inflammation and IgE production [ 18 ].

1.2. Mechanisms of Th2-Low Asthma

1.2.1. il-17.

IL-17 has been proposed to play an important role in Th2-low asthma [ 19 , 20 , 21 ]. Variants in the IL-17 pathway genes may be related to asthma pathology [ 22 , 23 ]. Higher levels of IL-17 are found in serum, sputum, and bronchoalveolar lavage fluid (BALF) of patients with asthma, which is associated with asthma severity [ 19 , 20 ]. There are several cell types secreting IL-17 cytokines. CD4 + Th17 cells are one of the major sources of IL-17. Other cellular sources include major histocompatibility complex class I-restricted CD8 + T-cells, Natural killer T cells, mucosal-associated invariant T (MAIT) cells, ILC3 cells, and B-cells [ 24 ].

The role of IL-17 cytokines in asthma is still under investigation. IL-17 cytokines may stimulate epithelial cells and fibroblasts to release neutrophil chemoattractants CXCL1/5/8 and granulocyte–macrophage colony-stimulating factor, which recruit neutrophils to the lungs. Furthermore, IL-17A, but not IL-17F, enhances airway smooth muscle contraction [ 21 ], migration [ 25 ], and proliferation [ 26 ], which facilitates airway hyperresponsiveness (AHR) and airway remodeling, key characteristics of asthma. However, it has been proposed that IL-17 cytokines are important for maintaining the integrity of the epithelium and IL-17 cytokines may play a protective role against asthma [ 24 ] ( Figure 2 ).

Mechanism of Th2-low asthma. Th17 cytokines: Bacteria promote Th17 cell differentiation via antigen-presenting cells (APCs). Variants in the IL-17 pathway genes also contribute to IL-17 upregulation. IL-17 can stimulate epithelial cells and fibroblasts to release neutrophil chemoattractants CXCL1/5/8 which recruit neutrophils to the lungs. Furthermore, IL-17A enhances airway smooth muscle contraction, migration, and proliferation, which facilitates AHR and airway remodeling, Th1 cytokines: Infection and epithelial injury promote Th1 cell maturation and secrete Th1 cytokines, including TNF-α and IFN-γ. TNF-α synergizes with IL-17 cytokines to promote neutrophil recruitment. Furthermore, TNF-α enhances airway smooth muscle contraction. IFN-γ and TNF-α upregulate Ca 2+ signaling in airway smooth muscle and induces AHR. In addition, IFN-γ promotes neutrophil recruitment in the presence of IL-17 cytokines.

1.2.2. Other Cytokines

It is known that Th1 cells secrete IL-2, interferon-γ (IFN-γ), and lymphotoxin-α and stimulate Th1 immunity, which is characterized by prominent phagocytic activity. However, recent studies suggest that some Th1 cytokines may contribute to asthma pathogenesis. Tumor necrosis factor-α (TNF-α) is a pleiotropic Th1 cytokine, which plays a role in the pathogenesis of inflammatory diseases, including allergy. Sputum TNF-α is elevated in neutrophilic and severe asthma [ 27 ]. TNF-α is proposed to synergize with IL-17 cytokines to promote neutrophil recruitment [ 1 , 24 ]. However, TNF-α may also promote the production of Th2 cytokines, such as IL-4, IL-5, and IL-13 [ 28 ]. Furthermore, TNF-α enhances airway smooth muscle contraction, which may contribute to the development of AHR [ 29 ] ( Figure 2 ).

IFN-γ, IL-1β, and TNF-α have been shown to upregulate the expression of CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase in airway smooth muscle cells, which may upregulate intracellular Ca 2+ signaling and induce AHR. Knockout (KO) of CD38 reduced AHR in a murine model of asthma [ 30 , 31 ]. In addition, IFN-γ promotes neutrophil recruitment in the presence of IL-17 cytokines [ 1 , 24 ].

1.3. Emerging Mechanisms of Asthma

Asthma has long been viewed as an inflammatory disease. However, there is accumulating evidence to suggest that inflammation-independent processes are also associated with asthma progression. For instance, recent studies demonstrate that protein kinases, adapter proteins, and other molecules contribute to asthma pathogenesis [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ] ( Figure 3 ).

Emerging mechanisms of asthma. Asthma has long been viewed as an inflammatory disease. However, there is accumulating evidence that inflammation-independent processes also contribute to asthma progression. Genetic variance and epigenetics (e.g., miRs) affect expression of proteins, including kinases, adapter protein, ORMDL3, Gasdermin B, and matrix metalloproteinases in lung tissues, which drive asthma progression.

1.3.1. Proteins Kinases

c-Abl (Abelson tyrosine kinase, Abl, ABL1) is a non-receptor tyrosine kinase that participates in the regulation of smooth muscle contraction, migration, and proliferation [ 38 , 41 , 42 , 43 , 44 , 45 ]. c-Abl is upregulated in asthmatic human airway smooth muscle (HASM) cells, which is regulated by epigenetic factors [ 46 , 47 ]. c-Abl KO or inhibition reduces asthma-like phenotypes in animal models of asthma [ 38 , 45 ]. Furthermore, c-Abl KO or inhibition diminishes Th2 cytokines in experimental asthma [ 38 , 45 ]. These results suggest that c-Abl is a Th2-regulatory protein rather than a Th2-dependent protein. Intriguingly, treatment with the c-Ab/KIT inhibitor imatinib relieves the symptoms of severe refractory asthma [ 48 ].

Polo-like protein kinase 1 (Plk1) is a serine/threonine kinase that plays a role in modulating smooth muscle contraction [ 37 , 49 ], proliferation [ 50 , 51 ], migration [ 50 ], mitosis [ 52 , 53 ], and apoptosis [ 40 ]. In asthmatic HASM cells, downregulation of miR509 leads to elevated Plk1 [ 50 ]. Smooth muscle conditional KO of Plk1 inhibits asthma progression in a murine model of asthma [ 52 ]. Plk1 may contribute to airway remodeling via promoting ASM proliferation/migration and inhibiting apoptosis [ 40 , 50 , 52 , 54 ]. However, Plk1 does not affect Th2 inflammation in experimental asthma [ 52 ].

p21-activated kinase (PAK) regulates smooth muscle contraction by modulating the vimentin network and paxillin complexes [ 54 , 55 ]. Furthermore, a PAK inhibitor or PAK KO protects mice from AHR and airway smooth muscle hyperactivity in vitro [ 56 ]. However, it is unclear whether PAK expression and activity are altered in the lungs or serum of asthmatics. Another protein kinase glycogen synthase kinase-3β (GSK-3β) is also linked to asthma pathology. Airway smooth muscle hyperplasia and hypertrophy correlate with GSK-3β phosphorylation in a mouse model of asthma [ 57 ]. GSK3 negatively regulates smooth muscle gene expression and hypertrophy. Phosphorylation of GSK3 disinhibits smooth muscle gene expression and promotes ASM hypertrophy and hyperplasia [ 57 , 58 ].

1.3.2. Adapter Protein

Abi1 (Abelson interactor 1) is an adapter protein that regulates cell migration [ 59 , 60 ], smooth muscle contraction [ 61 ], and cell proliferation [ 39 ]. The human Abi1 gene is localized in the Chromosome 10p21 region. Genome-wide association studies (GWAS) suggest that Chromosome 10p21 is adjacent to a susceptible locus for asthma and related traits [ 62 , 63 ]. Abi1 is upregulated in asthmatic HASM cells/tissues [ 39 ]. Loss-of-function studies suggest that Abi1 contributes to aberrant HASM cell proliferation and asthma phenotype in a murine model of asthma [ 39 ].

1.3.3. MicroRNAs (miRNAs)

miRNAs are evolutionarily conserved, 18–25 nucleotides, noncoding RNA molecules that control gene expression by binding to complementary sequences in the 3′ untranslated regions (3′ UTR) of target mRNAs, which degrade target mRNA and/or repress translation [ 64 ]. The levels of miR-203 are downregulated in human asthmatic ASM cells, which disinhibits c-Abl expression and promotes asthma development [ 46 , 65 ]. Moreover, the expression of miR-509 is lower in human asthmatic ASM cells, which is responsible for the upregulation of Plk1 and asthma progression [ 47 , 50 ]. miR-25 expression is associated with alterations in ASM cell phenotype, an important process for airway remodeling [ 66 ]. miR-144–3p has been shown to be associated with severe corticosteroid-dependent asthma [ 67 ].

1.3.4. Others

ORMDL3 and gasdermin B. GWAS suggest that chromosome 17q21 is linked to asthma [ 68 , 69 ]. Chromosome 17q21 contains a cluster of genes, including ORMDL3 and gasdermin B (GSDMB) [ 69 ]. ORMDL3 may contribute to asthma progression by modulating store-operated calcium entry and lymphocyte activation [ 70 ], eosinophil trafficking and activation [ 71 ], and sphingolipid homeostasis [ 72 ]. Gasdermin B may promote AHR and airway remodeling, without affecting airway inflammation via remodeling-associated gene expression [ 73 ].

Matrix Metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases with more than 20 isoforms. MMPs have been linked to asthma, which is isoform dependent [ 74 , 75 ]. Single-nucleotide polymorphisms (SNPs) in the gene encoding MMP-12 is associated with FEV1 in children and adults with severe asthma [ 76 ]. The SNPs in the MMP-12 promoter region increase MMP-12 expression, which may activate macrophages and promote asthma progression [ 74 ]. In addition, mast cell tryptase proteolytically activates pro-MMP-1 generated by ASM, which subsequently degrade the extracellular matrix and promote ASM cell growth and airway remodeling [ 77 ]. However, MMP-2 appears to have a protective role in asthma. Mice overexpressing human MMP-2 showed a significant reduction in AHR, Th2 cytokines, and IgE compared to their wild-type counterparts [ 75 ].

2. Biomarkers of Asthma

As mentioned above, biomarkers of a disease are traceable substances that are useful for diagnosis, classification, and treatment. Although the omics technologies (e.g., epigenomics, genomics, transcriptomics, proteomics, metabolomics, lipidomics, etc.) and microbiome have been proposed to serve as biomarkers for asthma [ 78 ], they are still in the early stage of research. In this review, we focus on clinically practical biomarkers collected from induced sputum, blood, exhaled gases, and bronchoscopic samples.

2.1. Th2-High-Related Biomarkers

2.1.1. sputum eosinophils.

Eosinophils in induced sputum provide important information on asthma phenotyping and understanding of asthma pathophysiology [ 79 ]. Increased sputum eosinophil levels (>3%) have been associated with high airway inflammation, frequent asthma exacerbation, and poor asthma control [ 80 , 81 ].

2.1.2. Blood Total Eosinophil Count (TEC)

TEC has also been considered as a non-invasive biomarker for eosinophilic inflammation [ 79 , 82 , 83 , 84 ]. The usage of blood eosinophil counts as a diagnostic biomarker for airway eosinophilia has been evaluated by assessing the relationship between blood and sputum eosinophil counts [ 85 , 86 , 87 , 88 ]. TEC increases ≥0.30 × 10 9 /L when Th2 lung inflammation and asthma exacerbations transpire. If a blood count is <0.15 × 10 9 /L, sputum eosinophilia may not be found, especially when FeNO is low (<25 ppb) [ 89 ]. However, higher TEC is also seen in patients with atopic dermatitis and other allergic diseases. Thus, the demonstration of eosinophilia is not a specific marker of Th2 lower airway inflammation. These caveats prompt physicians to use FeNO measurement, which is associated with airway inflammation [ 90 ].

2.1.3. Serum IgE

Serum IgE is an immunoglobulin, which induces type 1 hypersensitivity reactions and anaphylaxis. As described earlier, IgE also plays a key role in the pathogenesis of allergic asthma. Elevated levels of IgE are correlated with patients with asthma [ 91 ]. There is an association between IgE levels, skin testing, and lung function in asthmatics. Clinical studies show that asthmatics have an inverse relationship between IgE and FEV1/FVC ratio [ 92 ]. Various clinical trials have used IgE as a biomarker to identify Th2-high asthma. Omalizumab, a recombinant human anti-IgE antibody that binds to circulating IgE at the IgE receptor binding site, blocks the activation of the mast cells and basophils. A large phase III study that recruited over 500 patients with asthma found that IgE levels are from 30 to 700 IU/mL. Omalizumab treatment was able to reduce exacerbation rates and improve quality-of-life scores [ 93 ]. However, a Cochrane review published in 2014 on the use of omalizumab questions whether there is a clear threshold level of IgE for optimal efficacy. The authors note a wide spread in the mean serum IgE levels of patients included in clinical trials, ranging from 141.5 to 508.1 IU/mL [ 94 ].

2.1.4. Nitric Oxide

Nitric oxide is produced by airway epithelial cells as a result of IL-13-induced upregulation of nitric oxide synthase in the airway epithelium and is, therefore, a more specific marker of Th2 airway inflammation [ 95 , 96 , 97 ]. FeNO is a reproducible, easily measurable biomarker, indicative of AHR and a good predictor of inhaled corticosteroid (ICS) response [ 98 , 99 , 100 ]. FENO values between 25 ppb and 50 ppb (20–35 ppb in children) should be interpreted cautiously and with reference to clinical context. FENO greater than 50 ppb (>35 ppb in children) can be used to indicate that eosinophilic inflammation and, in symptomatic patients, responsiveness to corticosteroids are likely. However, FeNO may be affected by several confounders, including demographics, smoking, diet, nasal polyps, and atopic status [ 99 , 101 , 102 , 103 , 104 ]. Although most patients with raised FeNO respond to corticosteroids, some patients are resistant to corticosteroid treatment. Their FeNO is not suppressed and they have high Th2 cytokines and chemokines in sputum [ 90 ]. That said, FeNO level is a useful indication for Th2-high asthma and helps to use appropriate doses of inhaled ICS [ 105 ].

2.1.5. Periostin

Periostin is upregulated by recombinant IL-4 and IL-13 in cultured bronchial epithelial cells and bronchial fibroblasts [ 15 , 16 , 106 ]. Periostin is proposed as a surrogate marker of Th2 inflammation. Serum periostin levels are significantly higher in asthmatic patients with eosinophilic airway inflammation. A logistic regression model, including sex, age, IgE levels, blood eosinophil numbers, body mass index, FeNo levels, and serum periostin levels, in 59 patients with severe asthma, showed that the serum periostin level was the best predictor of airway eosinophilia [ 107 ].

2.1.6. Cytokines

Levels of IL-4, IL-5, and IL-13 in sputum and BALF are higher in asthmatics. TSLP, IL-33, and IL-25 in epithelium are elevated in asthmatic patients [ 106 ]. These cytokines are the gold standard to verify Th2-high asthma for clinical research. However, it may not be feasible for routine practice because of high costs.

These Th2-high biomarkers are being used to choose adequate biologic therapy and monitor the patients’ response to asthma treatment. For instance, higher levels in FeNO, blood eosinophils, and serum periostin (Th2-high asthma) are indications for use of the IgE antibody Omalizumab. Omalizumab treatment reduces asthma exacerbation rates and improves quality of life for this group of patients [ 93 ]. Lebrikizumab is an IgG4 humanized monoclonal antibody that specifically binds to IL-13 and blocks its function. Lebrikizumab administration was able to improve lung function. Patients with higher pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab [ 108 ]. Despite ICS therapy and an additional controller, some patients still had uncontrolled asthma. Lebrikizumab administration reduced exacerbation rate by 60% compared with a placebo in periostin-high patients and by 5% in periostin-low patients. However, lebrikizumab administration did not lead to clinically meaningful placebo-corrected improvements in asthma symptoms or quality of life [ 109 ].

2.2. Th2-Low-Related Biomarkers

2.2.1. sputum neutrophils.

Th2-low asthma includes late-onset asthma in middle-aged females, obesity-associated asthma, smoking-associated asthma, infection-associated asthma, and ozone-associated asthma [ 110 , 111 ]. Another common feature seen in Th2-low asthma is poor response to inhaled and oral corticosteroids [ 112 , 113 ]. Using induced sputum coupled with cytology, patients with Th2-low asthma are classed as paucigranulocytic and neutrophilic. In healthy subjects, neutrophils and macrophages are the major leukocytes in the induced sputum (median neutrophil percentage 37%). Cigarette smoking, ozone, infection, and endotoxin all increase sputum neutrophil counts. In asthma patients, sputum neutrophil count increased to 40–76% [ 111 ].

2.2.2. IL-17

As described earlier, IL-17 promotes neutrophilic inflammation in asthmatics. IL-17 levels in induced sputum, BALF, and bronchial biopsies have been found to be increased in severe asthma [ 19 , 20 ]. Due to technical challenge and costs, measurement of sputum IL-17 has not been widely used to characterize asthma phenotype.

2.2.3. Other Potential Biomarkers

TNF-α and IFN-γ contribute to the progression of Th2-low asthma [ 1 ]. IL-6 and C-reactive protein have been linked to severe asthma [ 111 ]. More studies are required to assess whether these potential biomarkers are practical in clinical settings.

2.3. Biomarkers Indicative of Airway Remodeling

2.3.1. bronchoscopy.

Airway remodeling is characterized by airway smooth muscle thickening, epithelial metaplasia, mucus hypersecretion, and basement membrane fibrosis with deposition of abnormal extracellular matrix [ 2 , 34 , 39 , 114 , 115 ]. Remodeling is seen in adults with chronic asthma and in childhood asthma as a result of chronic airway inflammation [ 114 , 116 , 117 ]. Considerable efforts have been made to identify potential biomarkers for structural changes in asthmatics; however, there is limited success. Bronchial biopsies are the gold standard to assess remodeling but are considered an invasive procedure. A study performed morphometric analysis on bronchial biopsy specimens before and after anti-IgE (Omalizumab) treatment to investigate changes in airway remodeling after 12 months of treatment [ 115 ]. This study showed reduced reticular basement thickening in some patients. Gal-3 is a regulatory molecule acting at various stages from acute to chronic inflammation and tissue fibrogenesis. Gal-3 can be considered a reliable biomarker to predict the extent of airway remodeling in severe asthma patients treated with omalizumab. In this study, Gal-3 was the most stable biomarker associated with the prediction of airway remodeling [ 118 ]. Additionally, because Gal-3 is a matrix protein, it is feasible to detect it in serum or urine [ 119 ].

2.3.2. YKL-40

YKL-40 is a chitinase-like protein that is associated with airway remodeling. In a study, YKL-40 levels in serum were increased in children with severe and therapy-resistant asthma compared to healthy children. Furthermore, serum levels of YKL-40 significantly correlate with bronchial wall thickness measured by high-resolution computerized tomography [ 120 ].

2.4. Genetic Risk for Asthma Development and Treatment

GWAS have implicated genetic variants in developing asthma. In particular, childhood asthma is associated with the 17q21 locus alleles. Polymorphisms of 17q21 are associated with an increased risk of exacerbations in children with asthma, despite ICS use. Single-nucleotide polymorphism (SNP) rs7216389 frequency was higher in East Asians, African Americans, and Hispanics, compared to patients of European ancestry [ 121 ]. In addition, the ORMDL3 gene is located at the 17q21 region and plays an important role in asthma pathogenesis. Asthmatic patients have higher levels of human lung ORMDL3 and ORMDL3 gene SNP rs8076131 [ 122 ]. IL-1receptor-like 1 (ST2) promotes asthma development by mediating the response to IL-33. ST2 SNPs rs13431828, rs1420101, rs1921622, and rs10204137 were related to lower efficacy of ICS in children and adolescents [ 123 ].

In addition to genetic risk, many environmental factors are also important risks for asthma, although most experts do not consider environmental risks to be “biomarkers’ for asthma. Allergens (e.g., house dust mite, pollen), pollutants, bacteria, viruses, and fungi are well-known environmental risks for asthma [ 124 , 125 , 126 ]. Exposure to different environmental factors may affect different mechanisms and asthma progression. For example, IL-17A is a potential mediator to link Candida albicans sensitization and poor outcomes for asthma [ 127 ].

3. Clinical Differences in Th2-High and Th2-Low Asthma

3.1. phenotypes of th2-high asthma.

Phenotypes of Th2-high asthma are classified into three groups: early-onset allergic asthma, late-onset eosinophilic asthma, and aspirin-exacerbated respiratory disease (AERD) [ 128 ].

3.1.1. Early Onset or “Extrinsic” Allergic Asthma

Early onset or “extrinsic” allergic asthma is the prototype of the asthma phenotype. The clinical presentation of child-onset allergic asthma ranges from mild to severe and it is unknown whether severe asthma is the result of evolution from a milder form or instead arises de novo as a severe type during childhood. This phenotype is different from Th2-high nonatopic asthma in terms of positive allergy skin tests and increased serum-specific IgE [ 129 ].

3.1.2. Late-Onset Eosinophilic Asthma

Late-onset eosinophilic asthma is a subgroup of Th2-high asthmatics with adult-onset disease, which has a distinct steroid-resistant eosinophilic phenotype of unknown molecular mechanism [ 130 ]. ICS therapy does not ameliorate airway Th2 inflammation in approximately half of this subgroup of asthmatics. Typically, these patients are older and have more severe asthma with persistent airflow obstruction [ 131 ]. The majority of these patients have comorbid chronic rhinosinusitis with nasal polyps, which generally precede asthma development. This phenotype is generally characterized by prominent blood and sputum eosinophilia, refractory to inhaled/oral corticosteroid treatment. Some of these patients have sputum neutrophilia in addition to eosinophilia, implicating Th2/Th17 inflammation [ 132 ]. This phenotype generally also has high FeNO and normal or elevated serum total IgE.

3.1.3. AERD

AERD is a subset of the late-onset phenotype, characterized by asthma, chronic rhinosinusitis with nasal polyps, and cyclooxygenase (COX)-1 inhibitor-induced respiratory reactions [ 128 ]. The mechanisms of this phenotype involve dysregulated arachidonic acid (AA) and leukotriene (LT) production. COX1/2 utilizes AA to synthesize PGE 2 , which is anti-inflammatory. In contrast, 5-lipooxygenase (5-LO) uses AA to synthesize LTs, which induce airway spam. Aspirin and other nonsteroidal anti-inflammatory drugs inhibit COX1/2, which shifts the balance to the 5-LO pathway and generates more LTs [ 128 ].

3.2. Phenotypes of Th2-Low Asthma

Based on clinical characteristics, Th2-low asthma phenotypes have been classified into obesity-associated asthma, smoking-associated asthma, and very-late-onset asthma [ 128 ].

3.2.1. Obesity-Associated Asthma

In general, obesity-associated asthma occurs in non-atopic and middle-aged women with severe symptoms, despite a moderately preserved lung function. This phenotype is not associated with eosinophilic lung inflammation. Obesity switches CD4 cells toward Th1 differentiation, which is associated with steroid refractory asthma [ 133 ]. Additionally, Th17 pathways, ILC3 that expresses both IL-17 and IL-22, and IL-6 have been associated with obesity-related asthma [ 128 , 134 ]. Consequently, IL-17, IL-22, and IL-6, rather than Th2 cytokines, may be clinically relevant in obese patients with severe asthma.

3.2.2. Smoking-Associated Asthma

The mechanisms underlying this phenotype involve oxidative stress, which induces epigenetic modifications and causes neutrophil and macrophage activation [ 135 ]. Smoking also enhances the risk of sensitization to allergens and increases total IgE. Recently, patients with smoking history and consequent airflow obstruction but also having overlapping features of asthma (bronchodilator reversibility, eosinophilia, and atopy) have been described as having “Asthma-COPD overlap syndrome (ACOS)”. The most recently published consensus of ACOS included six criteria, three of which are major (persistent airflow limitation, tobacco smoking, and previous asthma or reversibility > 400 mL FEV1) and three minor (history of atopy or rhinitis, significant bronchodilator reversibility, and peripheral eosinophilia). Although all COPD patients have not responded to the new biologic agents, the ACOS subset may actually benefit.

3.2.3. Very-Late-Onset Asthma

The age cutoff for the diagnosis of late-onset asthma is usually defined as >50–65 years [ 136 , 137 ]. The aging lung is associated with the loss of elastic recoil and immunosenescence, which may lead to decreased lung function. While mechanisms have not been fully understood, some studies suggest that older asthmatics have increased sputum neutrophilia, secondary to Th1 and Th17 inflammation [ 138 , 139 ].

4. Asthma-Associated Comorbidities

Asthma is often associated with a variety of comorbidities. Common reported asthma comorbidities include rhinitis, gastroesophageal reflux disease, nasal polyps, obstructive sleep apnea, hormonal disorders, vocal cord dysfunction, obesity, and psychopathologies [ 140 , 141 , 142 ]. These conditions may complicate the diagnosis and management of asthma or just coexist with asthma without obvious influence on this disease. These comorbidities could share a common pathophysiological mechanism with asthma or have different pathological processes. Future studies are required to understand how these comorbidities may interact with asthma.

5. Conclusions

Asthma is a heterogeneous lung disease with variable phenotypes and distinctive endotypes. In Th2-high asthma, IL-4 and IL-13 activate B cells, which produce IgE and sensitize mast cells. IL-5 promotes eosinophil recruitment to the lungs. In Th2-low asthma, IL-17 and TNF-α promote the recruitment of neutrophils to the lungs. Protein kinases, adapter protein, miRs, ORMDL3, and gasdermin B are newly identified molecules that contribute to asthma pathogenesis, independent of inflammation. Eosinophils, IgE, FeNO, and periostin are practical biomarkers for Th2-high asthma, whereas neutrophils are easily used for Th2-low asthma. Because asthma is a heterogeneous disease, more studies are required to identify new endotypes and new biomarkers to better diagnose and treat the illness.

Acknowledgments

We thank Thomas, J. Brown and Sarah McMullan for figure preparation.

Funding Statement

This work was supported by NHLBI Grants HL-110951, HL-130304, and HL-145392 from the National Institutes of Health (to Dale D. Tang).

Author Contributions

N.H. wrote the draft of the manuscript. M.A.P. and D.D.T. revised the manuscript. All authors reviewed the results and approved the final version of the manuscript.

Conflicts of Interest

The authors declare that they have no competing interests.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Asthma: Epidemiological Analysis and Care Plan Essay

Introduction, background and significance, surveillance and reporting, epidemiological analysis, screening and guidelines, plan: integrating evidence.

Asthma is an illness that disproportionately affects many adults and children globally. In 2019, 262 million people had asthma, causing 461 000 deaths (WHO, 2020). Scholars have done asthma-related research to provide information on causes, symptoms, therapies, and asthma mitigation. This study will describe asthma as a chronic condition, including its symptoms and signs, incidences, surveillance, reporting, epidemiological analysis, screening, prevention, and prevalence by state and national statistics.

Asthma is a lung disorder that makes it hard to breathe occasionally. Many people experience symptoms during childhood, though they can occur at any age. Asthma is caused by inflammation and subsequent muscular tightening around the narrow airways in the lungs, causing further narrowing of these passageways, leading to symptoms such as wheezing, coughing, chest tightness, and difficulty breathing (He et al., 2020). These symptoms and signs come and go and tend to be more intense at night or when exercising. Symptoms might be worsened by a variety of other typical triggers, including virus infections, weather fluctuations, fumes, smoke, dust, animal feathers and fur, tree and grass pollen, perfumes, and harsh soaps. Asthma has a variety of symptoms and pathogenesis, including acute, subacute, or chronic inflammation of the airways, intermittent blockage of airflow, and hyperresponsiveness of the bronchi (Sullivan et al., 2016). Mucus secretion and airway edema can lead to airflow restriction and bronchial reactivity (Sullivan et al., 2016). Mucus hypersecretion, epithelial desquamation, smooth muscle hyperplasia, airway remodeling, and mononuclear cells and eosinophils are all varying degrees.

Asthma prevalence has been shown to vary under various factors. It is higher in girls at 6.0% than in boys at 5.7% in the U.S., where it impacts more than 25 million people, including 8.4% of adults and 5.8% of children (CDC, 2020). There are 10.4% of women and 6.2% of males with asthma (CDC, 2020). Prevalence is higher among African Americans at 11.6% than Whites at 9.3% and lowest among Hispanics at 6.7% (CDC, 2017). In 2020, the CDC found that 7.4% of Texan adults and 7% of youngsters were currently dealing with asthma. Approximately ten individuals in the United States die every day from the illness (CDC, 2020). There were 232 fatalities in Texas in 2018, representing an annual mortality rate of 8.3 per 1,000,000 residents (CDC, 2019). The table below describes the CDC’s data about asthma prevalence in Texas and the United States.

Table 1: Prevalence Of Asthma In the U.S. & Texas

Information gathered through public health monitoring is used to inform and improve programs and policies to reduce disease incidence and mortality rates. Surveillance information on the prevalence of asthma in the United States is compiled from various sources, including the Behavioral Risk Factor Surveillance System (BRFSS) and the National Health Interview Survey (Pickens et al., 2018). The local burden of asthma has been estimated in several states and towns using surveys or administrative data, including Medicaid claims data and hospitalization (Benka-Coker, 2018). All these are accurate and credible sources of surveillance data and reports.

Cases of asthma have been identified using administrative data such as outpatient, pharmaceutical, or hospital billing data. Prevalence monitoring in schools has shown to be a fruitful exercise as most children are evaluated by school-based surveillance systems because they are present at school (Benka-Coker, 2018). In the U.S., laboratories and healthcare professionals report cases of communicable disease to state or local health centers as part of the country’s primary public health surveillance system, which relies on a passive, notifiable disease monitoring system (Haghiri et al., 2019). Compared to systems that rely on administrative data, this method often provides a timelier response and can facilitate the reporting of instances or clusters of cases.

Occupational asthma has prompted the creation of the Sentinel Event Notification System for Occupational Risks (SENSOR), which functions similarly to a system for reporting communicable diseases. It is currently conducted in ten states and includes a team of sentinel healthcare practitioners who are likely to meet an instance of occupational asthma reporting specified health events (Moloney, 2022). The results of SENSOR have led to the discovery of additional triggers for asthma in the workplace, but it does not collect data on the incidences of asthma in children or adult-onset asthma unrelated to work (Moloney, 2022). The SENSOR system offers helpful data on the prevalence of asthma in the workplace.

This section focuses on asthma – a chronic disease (What) that seriously affects children and adults (Who). Some of the most extensive asthma statistics come from high-income countries (Where) like the UK, Canada, Germany, New Zealand, and Australia, with severe asthma having a prevalence of 2-10% for the years 2017-2020 (When) (Stern et al., 2020). An estimated 23.4 million people have asthma, including 7 million children (Batra, 2022). If those without asthma are not counted, the prevalence of exercise-induced bronchial asthma is between 3 and 10%; if individuals with chronic asthma are included, it rises to 15% (Dharmage et al., 2019). Asthma morbidity and its prevalence appear to be on the rise, especially among children younger than six (Stothers, 2022). Interestingly, about two-thirds of those with asthma have their condition identified before they turn 18 (Stern et al., 2020). Therefore, prevalence changes with the country, sex, and even age.

Various factors contribute to developing asthmatic symptoms at any age (Why). While heredity plays a significant part in predicting susceptibility to developing asthma, environmental factors, rather than race, contribute more significantly to the disease (Dharmage et al., 2019). Air pollution, urbanization, passive smoking, and shifts in exposure to environmental allergens are among the factors that have been suggested as causes (Stothers, 2022). Most children with asthma see improvement or complete resolution of their condition by the time they are young adults because airway reactivity and poorer pulmonary function levels contribute to higher asthma rates in young patients (Stern et al., 2020). Hence, prevalence is higher among children than adults because most of the young ones will recover.

Asthma costs can be broken down into two categories: direct costs and indirect costs. Expenses considered “direct” are associated with hospital stays, doctor visits, nurses, ambulance rides, prescriptions, lab work, diagnostics, and preventative measures (Nunes et al., 2017). The costs associated with morbidity cannot be directly measured, such as the time and energy a parent or caregiver invests in caring for an asthmatic kid. Expenditures on prescription drugs and hospital stay accounted for the bulk of direct medical costs, significantly higher than indirect costs (Nunes et al., 2017). Direct medical expenditures may rise, but the total cost of treatment may go down if indirect costs fall by an even more significant amount due to better clinical outcomes.

Diagnosis begins with a discussion between the patient and the doctor regarding symptoms and general health. The doctor asks about existing symptoms and any possible triggers. The doctor carries out different types of screening, including spirometry, challenge tests, lung tests in children, and exhaled nitric oxide tests (Saglani & Menzie, 2019). For patients aged five years and above, spirometry is the standard diagnostic procedure that evaluates the inhaling and exhalation volumes and air rates (Louis et al., 2022). Asthma causes airway narrowing, so if the patient’s vital signs are below average for someone of the patient’s age, it may indicate that the patient needs medical attention. If the patient has asthma, the doctor may request that the patient inhale a medication to relax the patient’s airways before repeating a lung function test (Louis et al., 2022). Signs of marked improvement after this treatment suggest the possibility of asthma.

Since spirometry is a rather effective diagnostic tool, it is essential to analyze some of its characteristics. Thus, the research by Meneghini et al. (2017) showed that “the specificity of spirometric abnormality for detecting asthma was 90%, sensitivity was 23%, positive predictive value was 22%, and negative predictive value was 91%” (p. 428). These findings show that this test can be used only in specific cases like screening workers exposed to pollutants, but for most patients, this test is not enough because of its low sensitivity. However, since spirometry has a high NPV, it is likely that when the test is negative, a patient does not have asthma. Noticeably, spirometry shows higher levels of specificity than some other tools. Overall, spirometry is relatively cheap and rather common (Aaron et al., 2018). Patients not diagnosed using spirometry have higher overall costs than those who use this method.

The American Thoracic Society (ATS) and the European Respiratory Society (ERS) have published a standardized spirometry protocol. One indicator of airway obstruction is the fraction of one second’s forced expiratory volume divided by one’s forced vital capacity (FEV1/FVC) (Graham et al., 2019). Asthma is characterized by reversible physiological airflow restriction and airway diameter changes; spirometry should be the first step in the diagnostic process.

To control asthma, it is important to uncover and discuss its primary, secondary, and tertiary interventions that can be used by a nurse practitioner after graduation. The primary intervention is to position the patient properly, check the vital signs, and administer bronchodilators and oxygen if needed (Issel et al., 2021). These methods will help the nurse mitigate the asthma attack. Then, for the secondary intervention, the medical worker should use long-term control drugs like inhaled corticosteroids, prednisone, and budesonide (Sobieraj et al., 2018). These preventative asthma drugs target the inflammation of the airways, which is the root cause of asthma symptoms.

Finally, the education of patients is the tertiary method a nurse has to implement. Asthma interventions targeting teenagers and children must be customized to their specific conditions. Teens and kids in rural areas are more likely to benefit from interventions that include school-based health education programs and nurse services for asthma treatment (Horner et al., 2016). Rural children’s asthma outcomes are most likely to improve from interventions that go beyond encouraging strict adherence to prescribed medications. Positive results have been seen from interventions that boost healthcare providers’ understanding of asthma and its treatment (Estrada & Ownby, 2017). Programs with the most effects have trained primary care physicians and school nurses to better educate their patients about asthma and its management.

In order to ensure that the interventions have utility and that they are useful, I will incorporate their key aspects and components when treating the patients (Issel et al., 2021). I will also identify the patients that benefit from each type of intervention. I will also record and analyze specific conditions under which each intervention achieves maximum results (Issel et al., 2021). It will be possible to integrate health policy advocacy efforts, namely, the creation of school-based preventive programs to reduce the number of accidents among children.

In conclusion, the paper has discussed vital issues relating to asthma by collecting and interpreting data from previous research sources. The report has described and defined critical terms related to asthma, provided a background review, and discussed its signs and symptoms. The symptoms and signs identified are breathing difficulty, coughing, chest tightness, and wheezing (He et al., 2020). The paper has also discussed numerous approaches to monitor and survey disease prevalence, such as primary public health and sentinel surveillance system (Moloney, 2022). Epidemiological analysis, screening, and guidelines associated with asthma have also been discussed. Since statistics show that over 20 million people have asthma in America, this is a rather serious public health issue (Batra, 2022). Finally, the paper has provided a plan discussing the key interventions that can be incorporated to mitigate asthma. The interventions discussed are providing health care education, quick-relief efforts, and long-term asthma medications (Sobieraj et al., 2018). Healthcare education provided in schools also ensure that children and teenage cases are properly managed.

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• Chicago (A-D)
• Chicago (N-B)

IvyPanda. (2023, November 27). Asthma: Epidemiological Analysis and Care Plan. https://ivypanda.com/essays/asthma-epidemiological-analysis-and-care-plan/

"Asthma: Epidemiological Analysis and Care Plan." IvyPanda , 27 Nov. 2023, ivypanda.com/essays/asthma-epidemiological-analysis-and-care-plan/.

IvyPanda . (2023) 'Asthma: Epidemiological Analysis and Care Plan'. 27 November.

IvyPanda . 2023. "Asthma: Epidemiological Analysis and Care Plan." November 27, 2023. https://ivypanda.com/essays/asthma-epidemiological-analysis-and-care-plan/.

1. IvyPanda . "Asthma: Epidemiological Analysis and Care Plan." November 27, 2023. https://ivypanda.com/essays/asthma-epidemiological-analysis-and-care-plan/.

Bibliography

IvyPanda . "Asthma: Epidemiological Analysis and Care Plan." November 27, 2023. https://ivypanda.com/essays/asthma-epidemiological-analysis-and-care-plan/.

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Home — Essay Samples — Nursing & Health — Asthma — Asthma: Causes, Pathophysiology, and Treatment

Asthma: Causes, Pathophysiology, and Treatment

• Categories: Asthma

About this sample

Words: 635 |

Published: Apr 2, 2020

Words: 635 | Page: 1 | 4 min read

Table of contents

Introduction, pathophysiology, classification, management and treatment, lifestyle modification, medications, drug used to treat asthma, ipratropium bromide.

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