Introduction
Asthma is a heterogeneous disease characterized by chronic airway inflammation and influenced by environmental, neurological, and psychological factors. Chronic inflammation is associated with airway hyperresponsiveness often with widespread and variable reversible expiratory airflow limitation, thus resulting in recurrent wheezing, shortness of breath, chest tightness, and coughing.1 Cyclic asthma symptoms often lead to insomnia, daytime fatigue, reduced activity, and disruption to school and work.2 We summarized the prevalence, economic burden, neurophenotype, and future direction of asthma to emphasize its importance in the population. Relevant studies and publications were identified using the search terms asthma, prevalence, economic burden, and brain in the literature databases of MEDLINE, Web of Science, PubMed, and Google Scholar.
Prevalence of asthma
Asthma is one of the world’s fastest-growing diseases affecting roughly one-third of the global population. It is estimated that more than 339 million people worldwide suffered from asthma in 2016,3 of which mainland China accounted for 10%.4,5 Asthma affects approximately 14% of children worldwide, and approximately 2.5 million patients die each year from severe exacerbations.6
Table 1 summarizes the prevalence of asthma in various countries and regions. The prevalence of asthma in the United States increased by 15.1% in 2010, with children aged 0–17 years accounting for 27.2%.7 Bloom CI et al conducted a population-based cohort 2006–2016 based on United Kingdom electronic healthcare records and found overall asthma prevalence was 6.5% in 2016 (7.2% in 2006).8 According to the 2001–2016 National Health and Nutrition Examination Survey, 9.9% of women aged 18–44 years and 10.9% of pregnant women suffered from asthma with the highest prevalence in 2015–2016 (12.0%) and the lowest in 2003–2004 (8.6%).9 According to the Singapore National Health Survey, 10.5% of adults aged 18–69 years have asthma at some point in their lives.10 According to the 2012 Canadian Aboriginal Survey, the overall prevalence of lifetime asthma diagnosis was 16.0%.11 A study of 50,991 people in China found that the overall prevalence of asthma was 4.2%, only 28.8% of asthma patients had been diagnosed, and 15.5% of asthma patients had visited the emergency room at least once.12 Likewise, according to the results of three large-scale asthma surveys in China, the prevalence of asthma in childhood in China increased by nearly 50% every decade.13 Currently, there is a gap between the level of asthma treatment in China and the level of treatment recommended by the Global Asthma Prevention Initiative. In Beijing, China, only 34.9% of asthma patients were under control.14 In 2016–2017, a cross-sectional study in Qatar involving 54,704 children aged 5–12 years revealed a 6.1% prevalence of asthma.15 Sisay et al found prevalence of bronchial asthma among adult patients was 29.6% based on hospital based cross-sectional study involved in 257 participants.16 Raherison-Semjen pointed out that the prevalence of asthma in France has remained stable since 2006, and prevalence of lifetime asthma was 12.8% in 2018.17 According to a questionnaire-based study conducted in Hungary, the current prevalence of wheezing and physician-diagnosed asthma are 9.5% and 6.3%, respectively.18
Table 1Asthma prevalence rate in different countries
| Author | Country | Time horizon | Population | Rate (%) |
|---|
| 1 | Akinbami et al7 | United States | 2001–2010 | 25.7 million | 12 |
| 2 | Bloom et al8 | United Kingdom | 2006–2016 | – | 6.5 |
| 3 | Chuchalin et al9 | Russia | 2010–2011 | 7,164 | 25.7 |
| 4 | Karunanayake et al10 | Canada | 2012 | 24,803 | 16 |
| 5 | Marques et al11 | Brazil | 2012–2015 | 109,104 | 16 |
| 6 | Huang et al12 | China | 2012–2015 | 57 ,779 | 4.2 |
| 7 | Veettil et al15 | Qatar | 2016–2017 | 54,704 | 6.1 |
| 8 | Sisay et al16 | Ethiopia | 2018 | 257 | 29.6 |
| 9 | Raherison-Semjen et al17 | France | 2018 | 19,676 | 12.8 |
| 10 | Molnár et al18 | Hungary | 2018–2019 | 3,836 | 12.6 |
Economic burden of asthma
Asthma imposes a heavy financial burden on society and the healthcare system (Table 2).19–24 In the United States, the total cost of asthma treatment was US $81.9 billion in 2013, and the annual cost of asthma per person was US $3,266.19 According to a Japanese study, the cost of treating severe asthma is approximately double that of mild/moderate asthma with the average cost of hospitalized asthma patients reaching US $4,073.20
Table 2Average annual cost of asthma
| Author | Country | Year | Cost (USD) |
|---|
| 1 | Nurmagambetov et al19 | United States | 2013 | 3,266 |
| 2 | To et al20 | Japan | 2014–2018 | 4,073 |
| 3 | Wu et al21 | China | 2015 | 75 |
| 4 | Koul et al22 | India | 2018 | 556 |
| 5 | Bavbek et al23 | Turkey | 2016 | 4,369 |
| 6 | Sharifi et al24 | Iran | 2010–2012 | 367 |
In addition, Lee et al estimated the prevalence of asthma in South Korea at 3.7% using a national asthma sample analysis in 2014, and the total cost of asthma was US $645.9 million with direct and indirect costs of US $553.9 million and US $92 million, respectively.25 Finkelstein et al also found the annual economic burden of asthma in Singapore to be US $1.5 billion, 79 % of which was due to lost productivity, and the total annual cost of asthma in adults was estimated at US $1.25 billion.26 In 2015, the per capita direct medical expenses of children with asthma in China were approximately US $75, accounting for 1.06% of China’s per capita gross domestic product, or US $7,020.21 According to a report published in Lung India, the annual cost of treatment per asthma patient was US $240 resulting in a high cost of US $556 billion based on a conservative estimate of a 2% prevalence in India.22 Bavbek et al discovered that total direct medical costs per patient in Turkey were US $4,369.76 per year with medication/equipment (52.4%) being the main cost driver for severe asthma management, followed by hospitalization/intervention (26.4%), and comorbidities (15.2%).23 Moreover, the total annual cost of pediatric asthma in Iran was US $367 with medication being the most expensive (69%).24 A study of 20 institutions in Spain by Moreno et al found that the average direct cost, the cost per exacerbation, and average total annual cost were US $7,472, US $1,410, and US $8,554, respectively.27
Over the last few decades, the prevalence, morbidity, and mortality rates of childhood asthma have increased significantly worldwide. Although asthma is the most common chronic disease in children, underdiagnosis and undertreatment persist. Asthma prevalence varies widely around the world (Tables 1 and 2). Additionally, it varies by several orders of magnitude between countries. Asthma hospitalizations could increase due to increased asthma severity, poor disease management, and poverty. The economic burden of asthma is also high in developed countries, which consumes 1–2% of the healthcare budgets for asthma.
The brain is sensitive to hypoxia, and the lack of hypoxia caused by repeated asthma attacks could impair brain function, consequently leading to brain damage. Asthma patients have often been accompanied by various mental disorders, such as depression, anxiety, and panic attacks, which could aggravate asthma symptoms. Airway inflammation in asthma patients could be transmitted to the central nervous system resulting in the secretion of mediators in the airway nerves, which could play critical roles in neuroimmune interactions and worsen airway inflammation.28 Furthermore, psychological disorders, such as depression and anxiety, could exacerbate asthmatic bronchoconstriction by altering the function of the brain’s regions involved in respiratory control.29 These observations thus suggest that nerves could be involved in the modulation of asthmatic airway events, as the brain must transmit stress- and mood-related stimuli from the environment, hence signaling inflammatory mechanisms in the lungs and exacerbating the underlying disease.
Asthma neurophenotype
Therefore, it could be concluded that the neuron phenotype of asthma involves structural and functional changes in the brain’s regions, pathological cellular, and molecular immune processes, as well as also has external manifestations of psychological or neurological disease.30 Neurophenotype refers to the pattern of symptom expression caused by the interaction between the immune response that regulates inflammation and the neural process. It should be pointed out that the neurophenotype of asthma refers to neural processes, especially those related to mood, that regulate airway inflammation and clinical expression of the severity of asthma.31 Although relevant scholars have recognized the neurophenotype of asthma, current research on the pathophysiology of asthma and the manifestation of asthma symptoms has almost exclusively focused on the lung. This paper would describe the neural phenotype of asthma in terms of brain structural changes, molecular expression, and epidemiology.
Brain structural changes
Neuroimaging and clinical studies have revealed that the neurophenotypes of asthma patients include structural and functional changes (Table 3). According to Rosenkranz et al, the neurophenotype of asthma could be identified by the neural responses of the brain’s circuits known to be involved in emotional information processing.32 People with higher anterior insula activation had higher lung inflammatory signals in response to asthma-related psychological stimuli. Huang et al also conducted research based on functional magnetic resonance imaging (fMRI) and found the regional homogeneity values of the left posterior cerebellar lobe and left upper frontal gyrus among healthy people were significantly higher in asthmatic patients.32 In contrast, the values of the right middle temporal gyrus and right inferior temporal gyrus were lower. Likewise, Gao et al discovered that asthma patients had abnormal structural connectivity in the bilateral frontal gyrus, right temporal, parietal cortices, and limbic regions, which hinted those changes in the function of the emotion-related brain regions in asthma patients.33 Ritz et al found that asthma patients with high airway inflammation had reduced activation in many cortical and subcortical regions associated with emotional processing and respiratory control.34 Li et al discovered regional abnormalities in the left angular gyrus, right anterior cuneus, and inferior temporal gyrus within the default mode network based on a low-frequency fluctuation amplitude, degree centrality, and functional connectivity.35 A study involving 1,287 adults found that people with asthma had a significantly smaller hippocampal volume than people without the condition.36
Table 3Abnormal areas for asthma
| Authors | Tools | Abnormal areas for asthma |
|---|
| Huang et al32 | MRI | Cerebellum, frontal lobe, temporal lobe, and occipital lobe. |
| Gao et al33 | DIT | Bilateral frontal gyrus, right temporal and parietal cortices, and limbic regions. |
| Ritz et al34 | fMRI | Dorsal anterior cingulate cortex and frontal lobe. |
| Li et al35 | fMRI | Superior frontal gyrus, occipital lobes, and inferior temporal gyrus. |
| Carlson et al36 | MRI | Hippocampal volume. |
Table 3 summarizes the abnormal areas for asthmatic patients. We could find that the frontal lobe played a vital role in asthma-related neurophenotypes. Frontal lobe development is essential for acquiring, executing, and controlling a wide range of functions from basic motor response to complex decision-making. Disruptions in the fronto-subcortical circuitry that governs motivated behavior appear to contribute to a variety of developmental disorders, including attention-deficit/hyperactivity disorder and anxiety, as well as vulnerability to psychopathology.
Molecular expression
Rosenkranz et al found that emotional responses were associated with significant changes in the fMRI signals in the anterior cingulate cortex and insula, and emotional responses were negatively correlated with lung function in asthma patients.37 Furthermore, the induction of asthma-related psychological stimuli in the anterior insula increased the response to the inflammatory signals in the lungs, which correlated with disease severity. In chronic stress asthma patients, acute psychological stress exacerbated airway inflammation, which was associated with signal crossing interactions between the anterior cingulate cortex and the insula in response to psychological stress. During psychosocial stress induction, activation of the medial and anterior cingulate cortex was associated with increased expression of interleukin 23 subunit alpha and interleukin-1 receptor type 1 mRNA in the sputum cells of asthmatics after stress.38 Moreover, Caulfield et al found that brain stem serotonin transporter mRNA expression decreased by approximately 30% in adult mice that experienced an asthma attack during adolescence, while the hippocampal serotonin receptor 1A and corticotropin-releasing hormone receptor 1 expressions increased by approximately 50%.39
It is known that the occurrence of asthma is closely related to the peripheral immune and inflammatory pathway. Airway inflammation is one of the important clinical features for asthma. Under the interaction of autoimmunity and adaptive immunity, external antigen stimulation causes eosinophilia, type 2 helper T cells (Th2) to migrate to the airway epithelium and subcutaneous mucosa, and release interleukin (leukin), which leads to subepithelial fibrosis, bronchial remodeling, and airway hyperresponsiveness. In addition, some studies have confirmed that depression is an inflammatory disease.40 The level of peripheral immune inflammation in depressed patients is significantly higher than that in healthy people,40 including the increased expression of proinflammatory cytokines and their receptors.41 Such a disturbed level of peripheral immune inflammation could directly affect the structure and function of the brain. Notably, stress is a common risk factor for asthma and depression. For asthma, stress does not simply suppress the immune system of asthmatic patients, but breaks the balance of the Th1/Th2 cytokines, thus making them shift to the Th2 type.42 For depression, stress (especially early life events and lack of interpersonal interaction) could enhance the inflammatory response. The high comorbidity rate of asthma and depression highly would suggest that there could be some common pathogenesis between them. The relationship between asthma and its neurophenotype might be explained by the hypothalamic-pituitary-adrenal axis (HPAA). For example, some researchers found that mothers who experienced perinatal stress had a significantly increased risk of asthma in their offspring.43 Hence, the HPAA would be an important component of the stress system, and the release of proinflammatory cytokines during asthma inflammation could cause the activation of the stress system. In addition, stress and negative emotions increase inflammatory mediators. Depression related studies also suggested that depression was associated with the HPAA dysfunction, and the levels of stress hormones, such as cortisol, were significantly increased in patients with depression. These findings together suggested that inflammatory cytokines and HPAA activity were promising biomarkers for asthma with depression.
Epidemiology
A recent meta-analysis showed that anxiety disorders were prevalent in nearly 23% of asthmatic adolescents compared with a prevalence of 7–8% in the general youth population.44 Adolescents with asthma also had higher morbidity rates and were more likely to suffer from a major depressive disorder than the control. Additionally, Scott et al found that age- and sex-adjusted pooled estimates of the prevalence of mental disorders were 1.6 for asthma, 1.5 for anxiety disorders, and 1.7 for alcohol use disorders compared with patients without asthma.45 A study evaluating the relationship between asthma and anxiety in Japanese elementary school students showed that the multifactor PR for anxiety in asthmatic boys was 1.56 compared to non-asthmatic boys.46 This association was more pronounced in older boys, where PR was 1.32 for younger boys, and 1.87 for older boys. A multi-ethnic adult survey also showed an association between asthma and mental disorders, particularly anxiety disorders (odd ratio (OR) = 2.7), depression (OR = 1.6), and bipolar disorder (OR = 2.1).47 Likewise, a study involving 1,358 adults with asthma and non-asthmatic cross-sectional studies showed that severe asthma increased the odds of depression by 53%. In contrast, mild to moderate asthma was associated with an 11-fold increased likelihood of suicidal ideation.48 Adolescents with asthma had a 22.7% prevalence of anxiety disorders and higher levels of anxiety symptoms than adolescents without asthma.49
Future direction
In summary, the incidence of asthma is becoming more and more serious, and the population base of asthma patients is large and growing rapidly. Consequently, the severe situation of the heavy economic burden and low degree of disease control would affect the living standards and mental health of the patients. Asthma hypoxia might also cause brain damage, initiate mental disorders, and induce abnormal brain electrical activity. Electroencephalogram (EEG) signals could capture the abnormal areas of the brain and quantify the changes from the perspective of bioelectrical signals.
An EEG is an essential bioelectrical signal of the human body, which contains a large amount of physiological information about the body. It can be obtained by collecting and recording potential changes in the superficial skin of the head (Fig. 1). Brain signals change with the cognitive processes of the brain, which could respond quickly to external stimuli and provide accurate human data. Furthermore, EEG signals contain a large amount of physiological information and disease information, which could provide a basis for the diagnosis or effective treatment for certain brain diseases.50
However, to date, only a few studies on EEG signals related to asthma have been reported. The respiratory associated evoked potentials (REP) study showed that six out of 11 patients with severe asthma were missing P1 in early REP.51 Nicot et al found less REP component in children with asthma than in healthy subjects.52 Asthma patients exhibited significant enhancement of power and functional connectivity in both the default mode network and the resting salient state network. Several studies have also shown that EEG signals could help to analyze other respiratory-related diseases.53 EEG signals have been used for sleep monitoring, especially for lung diseases, such as chronic obstructive pulmonary disease (OSA). Moreover, one study has shown that OSA patients with hypoventilation had changes in awake EEG with increased EEG power, increased microstates C, and decreased microstates D.54 A systematic study of spindle oscillations in patients with sleep disorders showed lower spindle wave density/spindle frequency activity and slower mean spindle frequency than controls. Compared with other brain examinations, EEG signals are cheaper, easier to operate than magnetic resonance imaging and positron radiography, and non-invasive real-time access to EEG signals. The authors think that EEG signals could be used to study the neurophenotype of asthmatic patients with better performance.
Conclusions
Asthma is one of the world’s fastest-growing diseases affecting roughly one-third of the global population. This paper reviewed the prevalence, economic burden, and neurophenotype of asthma. We found the frontal lobe plays an essential role in asthma-related neurophenotypes. Additionally, an EEG could be used as one of the tools to analyze the neurophenotype of asthma.
Abbreviations
- EEG:
electroencephalogram
- fMRI:
functional magnetic resonance imaging
- HPAA:
hypothalamic-pituitary-adrenal axis
- OR:
odd ratio
- OSA:
obstructive pulmonary disease
- REP:
respiratory associated evoked potentials
- Th2:
type 2 helper T cells
Declarations
Acknowledgement
The authors would like to thank all the reviewers who participated in the review.
Funding
The research was supported by the project of the Natural Science Foundation of Shandong Province (ZR2020QF024; ZR2021QH290), Jinan 20 Universities (2019GXRC040), Jinan 5150 Program for Talents Introduction, Major Basic Research Project of Shandong Natural Science Foundation (ZR2021ZD40), Key Research and Development Plan of Shandong Province (2021CXGC011304), and Shandong Institute of Advanced Technology, Chinese Academy of Sciences (YJZX003, YQCX20220106).
Conflict of interest
The authors declare that they have no conflicts of interest.
Authors’ contributions
Guarantor of the integrity of the entire study (CC); study concept and design, and manuscript editing (CC and FLP); literature research (GQZ, XWW, XKZ, and ZYW); data acquisition (YS, JPA, and CC); data analysis (CC, FLP, and DYL); manuscript preparation (CC, FLP, and ZLZ); manuscript revision/review (CC). All authors participated in this study and consented to publish this article in the Journal. The contribution list is shown in the following form.