The word asthma is derived from the ancient Greek, aazein, meaning “gasping” or “panting” . (Marketos et al., 1982) Asthma is a potentially serious chronic disease that imposes a huge burden on patients, their families and the community. It causes respiratory symptoms, limitation of activity and flare-ups that sometimes require urgent emergency management and may be fatal. Fortunately, asthma can be treated effectively, and most patients can achieve good asthma control. (GINA, 2018)
The association between bronchial asthma and obesity has been illustrated by many studies in both children and adults. However, the mechanisms behind this association are still not fully understood . (Ziora et al., 2013)
Different mechanisms have been suggested including systemic inflammation and adipocyte-derived factors such as the pro-inflammatory and anti-inflammatory adipokines which include adiponectin, resistin and others. (Samaras et al., 2010)
Several studies suggest that there are at least two distinct phenotypes of asthma in obesity , . (Wenzel, 2012; Farzan, 2013) The obese state alters both early onset allergic asthma and leads to the development of a novel form of late onset asthma, in part due to obesity. , , (Sideleva et al., 2012, 2013, 2014)
Patients with the atopic phenotype are likely to have pathophysiology consistent with early onset allergic asthma that is complicated by the development of obesity. Early onset allergic asthma is characterized by TH2 driven lymphocytic inflammation with increases in cytokines such as IL-4 and IL-5 that promote airway eosinophilia and IL-13 leading to mucus hypersecretion. (Hessel, 2010; Wenzel, 2012)
Adipose tissue produces several cytokines and adipokines which may have a synergistic adverse effect on the airways. Cytokines produced by adipose tissue include plasminogen activator inhibitor-1, monocyte chemotactic factor-1, interleukins 6 and which may affect the airway such as plasminogen activator inhibitor-1, monocyte chemotactic factor-1, IL-6 and 8, and adipokines such as leptin and adiponectin. The precise role of many of these mediators in the pathogenesis of allergic airway disease is not well known however, several studies have shown the potential role of adiponectin (which is decreased in obesity) and leptin (which increases in obesity) in allergic asthma. (Sideleva et al., 2012, 2013, 2014)
The second phenotype relates to obese patients with later onset of asthma and lower prevalence of allergic disease. These individuals have late onset asthma, in which obesity plays a role. Meta-analyses demonstrate a direct correlation between obesity and increased risk of the developing non-atopic asthma characterized by this phenotype. (Beuther and Sutherland, 2007)
This type of asthma is currently poorly understood but appears to be characterized by lower markers of airway eosinophilia and inflammation than those of early onset allergic asthma. Additionally, late-onset, non-atopic form of asthma is more common in women than men. (Jensen et al., 2012)
Several factors, both molecular and mechanical, could contribute to innate increases in airway reactivity and lung function with obesity. In addition to the airway hyper-responsiveness caused by the biochemical effects of adipose related cytokines and adipokines described earlier, mechanical changes in lung function and airways likely play an important role. (Jensen et al., 2012)
Bronchial Asthma
Asthma is chronic disorder of the airways that involves a complex interaction of bronchial hyper responsiveness, airflow obstruction and underlying inflammation. This leads to clinical symptoms of airway narrowing (bronchoconstriction) in response to exposure to a variety of stimuli including allergens or irritants. Allergen-induced bronchoconstriction results from an IgE dependent release of mediators from mast cells that includes histamine, leukotrienes, tryptase, and prostaglandins that directly stimulate airway smooth muscles. (EPR3, 2007)
Asthma can be classified clinically based on various parameters including atopic state of the individual, the degree of airway obstruction and the nature of trigger factors. the classification into atopic or non-atopic asthma is based on the presence or absence of clinical symptoms precipitated by one or more aeroallergens, supported by the presence of allergen specific antibodies as evidenced by skin prick with or without serological tests. (Pillai et al., 2011)
Definition of asthma
Asthma is a heterogeneous disease that is characterized by chronic inflammation of the airways. It is diagnosed by history of respiratory symptoms as wheezes, shortness of breath, chest tightness and cough that vary over time and in intensity, in addition to variable expiratory airflow limitation. These variations are often triggered by factors such as exercise, allergen or irritant exposure, change in weather, or viral respiratory infections. These features usually persist, even when symptoms are absent, or lung function is normal, but may normalize with treatment. (GINA, 2018)
Epidemiology
Prevalence and incidence
On a systematic review of asthma prevalence in Africa published between the years 1990 and 2012, the prevalence of asthma was 13.9% among children An Egyptian study estimated that the prevalence of asthma in total population in Egypt was 9.1%. The asthma was more prevalent among males (11.5%), than females (7.1%) . (Mansour et al., 2014)
The global prevalence of asthma in adults was estimated to be 4.3%. The prevalence of asthma varied widely amongst the 70 participating countries, ranging from 0.2% in China to 21.0% in Australia. (Teresa et al, 2012)
Gender
Asthma has a higher prevalence in boys than in girls before puberty, but among adults; epidemiological studies have demonstrated that the prevalence of asthma is higher among females than among males .(Baldaçara and Silva, 2017) No single straight forward mechanism can explain the gender differences found in asthma. It is still unclear why male predominance of asthma reverses after puberty; however, it is likely that hormonal changes contribute to genetic susceptibility. (Mansour et al., 2014)
Race
Racial/ethnic differences in asthma frequency, illness and death are highly connected with poverty, pollution, indoor allergens, not enough patient education and poor health care. The rate of asthma and the prevalence of asthma episodes is highest among Puerto Ricans compared to all ethnic groups in USA. (CDC, 2018)
African-American children have the highest prevalence of asthma. They are three times more likely to stay in the hospital due to asthma and have higher death rates especially women than other races or ethnicities. (CDC, 2018)
Obesity
During the years from 2011 to 2014, Prevalence of asthma according to center of disease control was significantly higher among adults with obesity (11.1%) compared with adults in normal weight (7.1%) and overweight (7.8%) categories . (Akinbami and Fryar, 2016)
Pathophysiology of Asthma
Airway narrowing
Asthma is a chronic inflammatory airway disease that results in narrow airway lumen. The airway narrowing is caused by increased mucus secretion as well as bronchial wall thickening due to edema, smooth muscle hypertrophy, and subepithelial fibrosis. The mechanisms that underlies these changes are diverse and heterogeneous. They are driven by different immune cells; mainly T-helper cells (Th2, Th17, Th1), mast cells, eosinophils, and neutrophils; as well as structural cells such as epithelial cells, myofibroblasts and smooth muscles. (Pavord et al., 2018) These mechanisms are classified into four categories.
Type 2 eosinophilic inflammation:
This is the most common type and includes at least 60% of all asthma patients. It is defined by sputum eosinophilia of ≥2% of leukocytes in a sample. Patients frequently have blood eosinophilia of ≥300/μl. Eosinophils secrete mediators such as major basic protein and eosinophil cationic protein that can cause bronchial epithelial damage and fibrosis. Those patients usually respond well to inhaled corticosteroids (ICS), especially if they have mild or moderate disease. It is further subdivided into two types: (Pavord et al., 2018)
Early-onset allergic eosinophilic airway inflammation (extrinsic asthma):
This type usually starts in childhood and can be triggered by allergen exposure. Allergens are taken up by dendritic cells and presented to naive T-cells that develop into Th2 cells characterized by the secretion of type 2 cytokines: interleukin (IL)-4, IL-5, and IL-13. IL-4 and IL-13 are necessary for specific B-cell activation and switching into immunoglobulin E (IgE)-producing cells. IgE binds to its high affinity receptor on mast cells. Subsequent cross-linking of IgE molecules by the allergen will lead to mast cell degranulation and release of mediators, such as histamine and tryptase as well as type 2 cytokines. In addition, IL-13 causes smooth muscle and goblet cell hyperplasia. On the other hand, IL-5 is essential for eosinophil development and maturation and contributes with certain other chemokines to their recruitment to the bronchial airways. , (Lambrecht and Hammad, 2015; Del Giacco et al., 2017)
Late-onset nonallergic eosinophilic airway inflammation (intrinsic asthma):
This type usually starts during adulthood. Patients typically have no allergies but usually more severe airway limitation and airway hyperresponsiveness (AHR). It is triggered by microbes (bacteria and viruses), pollutants, and irritants. Bronchial epithelial cells will subsequently release IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) that will stimulate innate lymphoid cells type 2 to release IL-5 and IL-13. (Brusselle et al.,2013)
Neutrophilic inflammation
It variably defined as neutrophils of ≥40%–60% of leukocytes in an induced sputum sample. It is less clearly characterized and involves release of Th1-and Th17-related cytokines and IL8 and Granulocyte-macrophage colony-stimulating factor (GM-CSF) that attracts neutrophils to the airways. It is triggered by infections, irritants, and tobacco smoke and may be a manifestation of the use of steroids in patients with eosinophilic inflammation. Those patients are mostly adults and do not respond to ICS as well. (Amelink et al., 2013)
Mixed inflammation
This type has features of both eosinophilic and neutrophilic inflammation, including their cytokines profile. It is less common than the two previous types and tends to be more severe and more difficult to treat. (Papi et al.,2018)
Paucigranulocytic phenotype
In this form, there is not as much inflammation. The airway limitation is supposedly driven by other mechanisms. It is the least common and patients usually have milder disease. (Israel and Reddel, 2017)
Airway hyperresponsiveness
This is a major feature of all asthma phenotypes. Its mechanisms and mediators are poorly understood. It worsens during and immediately after asthma attacks. It is usually worse in patients with severe asthma. However, it does not correlate well with markers of inflammation. Smooth muscle hypertrophy and neurohumoral factors may play a role in determining AHR. (Park et al., 2012)
Airway remodeling
This is a major feature of asthma that starts early in the disease and causes incomplete reversibility by bronchodilator. It is characterized by bronchial epithelial damage, thickening of the basement membrane, and muscle hypertrophy. (Brightling et al., 2012) It is influenced by ongoing airway inflammation and recurrent bronchoconstriction. (Grainge et al., 2011)
Mortality and Morbidity of Asthma
Generally, asthma ranked 28th among the leading causes of disease burden and 27th in low- and middle-income countries. More than half (56%) of the global burden of asthma was due to 13.2 million Years of Life lived with Disability (YLD). This represents an increase in the age- standardized rate of YLD 3% due to asthma since 2006. This total disease burden is unchanged since 1990, despite the increase in total world population over time. (Vos et al., 2017)
Worldwide, there were 10.5 million years of life lost (YLL) attributed to asthma-related deaths. In 2016, asthma ranked 23rd (global) and 31st (LMICs) among the leading causes of premature mortality (YLL). (Naghavi et al., 2016)
Asthma phenotypes
Asthma phenotypes are the set of observable characteristics of an individual resulting from the interaction between its genotype and the environment. Dividing asthma into phenotypes helps to separate the disease into identifiable and treatable traits and to understand the course of the disease and its response to treatment, further enabling practice of precision medicine. , (Chung, 2016; Pavord et al., 2018)
Haldar et al. categorized asthma into five phenotypes through cluster analysis by targeting a primary and a secondary care asthma group inclusive of heavy asthma. (Haldar et al., 2008)
Group 1: Early‐onset atopic asthma (early age onset, atopic type): respiratory tract reversibility and eosinophilic inflammation were strong. Deterioration repeatedly occurs.
Group 2: Obese, non-eosinophlic asthma: Inflammation is not common and occurs mostly in overweight woman.
Group 3: Benign asthma: Control of symptoms, inflammation and prognosis is good.
Group 4: early symptom predominant asthma (early age onset, symptom priorities type): Both inflammation and reversibility are not common. symptoms are strong and there is tendency toward overtreatment.
Group 5: Inflammation predominant asthma: Although eosinophilic inflammation is predominant, symptoms are not prevalent, and treatment response is insufficient. This type is more common in men . (Haldar et al., 2008)
Also, the Severe Asthma Research Program (SARP) recognized five asthma phenotypes among adult patients with mild, moderate and severe asthma. They included: (Moore et al., 2010)
Cluster 1: Early‐onset atopic asthma. Mild symptoms of asthma
Cluster 2: Early‐onset atopic asthma (the largest cluster). Increased use of controllers compared with Cluster 1
Cluster 3: Late‐onset asthma. Mostly non-atopic. Mostly older obese women (the mean BMI is 33). This cluster is equivalent to Group 2 by Haldar et al.
Cluster 4: Early‐onset atopic asthma. Severe symptoms of asthma. This cluster is equivalent to Group 1 by Haldar et al.
Cluster 5: Late‐onset atopic asthma. Severe symptoms of asthma. Less responsive to bronchodilators. This type is characterized by chronic airflow obstruction . (Moore et al., 2010)
Another SARP study of children found 4 clusters: 1) later-onset with normal lung function, 2) early-onset atopic with normal lung function, 3) early-onset atopic with mild airflow limitation, and 4) early-onset with advanced airflow limitation . (Fitzpatrick et al., 2011).
These unbiased phenotypes overlap with previously known phenotypes, (late onset eosinophilic and early onset atopic/allergic), supporting the identification of these phenotypes in particular , . (Wenzel et al., 1999; Miranda et al., 2004)
Risk Factors Affecting Expression of Asthma
The world is in the middle of a major obesity epidemic, nearly 40% of the adult population is obese. (Hales et al., 2018) Obesity is a major risk factor for asthma and is particularly associated with poorly controlled asthma. (Dixon and Poynter, 2016) Although many different factors could contribute to the pathogenesis of asthma in obesity, changes in dietary composition and metabolic factors directly affect airway reactivity and airway inflammation. (Peters et al., 2018)
One additional link between obesity and asthma is adipokines and their effects on airway inflammation. Adipose tissue is a metabolically active tissue participating in energy homeostasis and immune responses. (Muc et al., 2014).
Diet
Many studies discussed the role of diet in asthma management. In a study by Wood et al., participants on the high fruit and vegetable diet had reduced asthma exacerbations during the time of the study. (Wood et al., 2012) Also, Ma et al.20 performed a 6-month controlled study targeting improved dietary quality versus maintaining usual diet. In this pilot study with 90 participants, better dietary quality tended to improve asthma control and asthma quality of life. (Ma et al., 2016)
Sexton et al., performed a small 12-week pilot study in 38 patients with asthma and found that implementing a Mediterranean diet might have some efficacy in asthma, although it did not achieve statistical significance in this small study. (Sexton et al., 2013)
Smoking
In a recent study by Selya et al., smoking within 5 min of waking was associated with a four-fold increase in the odds of lifetime asthma. (Selya et al., 2018) Smoking asthmatics respond less to existing asthma therapies and are usually more resistant to inhaled corticosteroids. Also, smoking asthmatics have increased exacerbations, lung function decline, and more asthma symptoms. (Polosa and Thomson, 2013)
Asthmatic smokers may represent a unique asthma endotype because of the specific biological mechanisms arising from an interaction between smoking, genetics, and environmental factors. (Soler and Ramsdell, 2015)
Furthermore, smoking during pregnancy is an asthma's predisposing factor at all ages. Smoker mothers were three times more likely to have children with asthma than those who did not smoke. (Maggina et al., 2014)
Family history of atopy and the sibling effect
Family history of atopy is the strongest risk factor for childhood asthma. Asthma in parents or siblings increased the risk of childhood asthma in offspring up to adulthood. (Paaso et al., 2013)
Genetic
The genetics of asthma has been extensively studied. So far, associations between 78 single nucleotide polymorphisms (SNPs) and asthma have been identified in 28 asthma gene wide associated studies (GWAS), yet very few studies were replicated across other populations . (Ding et al., 2013)